Feeds:
Posts
Comments

Archive for the ‘Epigenetics and Cardiovascular Risks’ Category

2021 Virtual World Medical Innovation Forum, Mass General Brigham, Gene and Cell Therapy, VIRTUAL May 19–21, 2021

The 2021 Virtual World Medical Innovation Forum will focus on the growing impact of gene and cell therapy. Senior healthcare leaders from all over look to shape and debate the area of gene and cell therapy. Our shared belief: no matter the magnitude of change, responsible healthcare is centered on a shared commitment to collaborative innovation–industry, academia, and practitioners working together to improve patients’ lives.

About the World Medical Innovation Forum

Mass General Brigham is pleased to present the World Medical Innovation Forum (WMIF) virtual event Wednesday, May 19 – Friday, May 21. This interactive web event features expert discussions of gene and cell therapy (GCT) and its potential to change the future of medicine through its disease-treating and potentially curative properties. The agenda features 150+ executive speakers from the healthcare industry, venture, startups, life sciences manufacturing, consumer health and the front lines of care, including many Harvard Medical School-affiliated researchers and clinicians. The annual in-person Forum will resume live in Boston in 2022. The World Medical Innovation Forum is presented by Mass General Brigham Innovation, the global business development unit supporting the research requirements of 7,200 Harvard Medical School faculty and research hospitals including Massachusetts General, Brigham and Women’s, Massachusetts Eye and Ear, Spaulding Rehab and McLean Hospital. Follow us on Twitter: twitter.com/@MGBInnovation

Accelerating the Future of Medicine with Gene and Cell Therapy What Comes Next

https://worldmedicalinnovation.org/agenda/

Virtual | May 19–21, 2021

#WMIF2021

@MGBInnovation

Leaders in Pharmaceutical Business Intelligence (LPBI) Group

will cover the event in Real Time

Aviva Lev-Ari, PhD, RN

Founder LPBI 1.0 & LPBI 2.0

member_60221522 copy

will be in virtual attendance producing the e-Proceedings

and the Tweet Collection of this Global event expecting +15,000 attendees

@pharma_BI

@AVIVA1950

LPBI’s Eighteen Books in Medicine

https://lnkd.in/ekWGNqA

Among them, books on Gene and Cell Therapy include the following:

Topics for May 19 – 21 include:

Impact on Patient Care – Therapeutic and Potentially Curative GCT Developments

GCT Delivery, Manufacturing – What’s Next

GCT Platform Development

Oncolytic Viruses – Cancer applications, start-ups

Regenerative Medicine/Stem Cells

Future of CAR-T

M&A Shaping GCT’s Future

Market Priorities

Venture Investing in GCT

China’s GCT Juggernaut

Disease and Patient Focus: Benign blood disorders, diabetes, neurodegenerative diseases

Click here for the current WMIF agenda  

Plus:

Fireside Chats: 1:1 interviews with industry CEOs/C-Suite leaders including Novartis Gene Therapies, ThermoFisher, Bayer AG, FDA

First Look: 18 briefings on emerging GCT research from Mass General Brigham scientists

Virtual Poster Session: 40 research posters and presenters on potential GCT discoveries from Mass General Brigham

Announcement of the Disruptive Dozen, 12 GCT technologies likely to break through in the next few years

AGENDA

Wednesday, May 19, 2021

8:00 AM – 8:10 AM

Opening Remarks

Welcome and the vision for Gene and Cell Therapy and why it is a top Mass General Brigham priority. Introducer: Scott Sperling

  • Co-President, Thomas H. Lee Partners
  • Chairman of the Board of Directors, PHS

Presenter: Anne Klibanski, MD

  • CEO, Mass General Brigham

3,000 people joined 5/19 morning

30 sessions: Lab to Clinic,  academia, industry, investment community

May 22,23,24, 2022 – in Boston, in-person 2022 WMIF on CGT 8:10 AM – 8:30 AM

The Grand Challenge of Widespread GCT Patient Benefits

Co-Chairs identify the key themes of the Forum –  set the stage for top GCT opportunities, challenges, and where the field might take medicine in the future. Moderator: Susan Hockfield, PhD

  • President Emerita and Professor of Neuroscience, MIT

GCT – poised to deliver therapies

Inflection point as Panel will present

Doctors and Patients – Promise for some patients 

Barriers for Cell & Gene

Access for patients to therapies like CGT Speakers: Nino Chiocca, MD, PhD

  • Neurosurgeon-in-Chief and Chairman, Neurosurgery, BWH
  • Harvey W. Cushing Professor of Neurosurgery, HMS

Oncolytic virus triple threat: Toxic, immunological, combine with anti cancer therapies

Polygenic therapy – multiple genes involved, plug-play, Susan Slaugenhaupt, PhD

  • Scientific Director and Elizabeth G. Riley and Daniel E. Smith Jr., Endowed Chair, Mass General Research Institute
  • Professor, Neurology, HMS

Ravi Thadhani, MD

  • CAO, Mass General Brigham
  • Professor, Medicine and Faculty Dean, HMS

Role of academia special to spear head the Polygenic therapy – multiple genes involved, plug-play, 

Access critical, relations with IndustryLuk Vandenberghe, PhD

  • Grousbeck Family Chair, Gene Therapy, MEE
  • Associate Professor, Ophthalmology, HMS

Pharmacology Gene-Drug, Interface academic centers and industry

many CGT drugs emerged in Academic center 8:35 AM – 8:50 AM FIRESIDE

Gene and Cell Therapy 2.0 – What’s Next as We Realize their Potential for Patients

Dave Lennon, PhD

  • President, Novartis Gene Therapies

Hope that CGT emerging, how the therapies work, neuro, muscular, ocular, genetic diseases of liver and of heart revolution for the industry 900 IND application 25 approvals Economic driver Skilled works, VC disease. Modality one time intervention, long duration of impart, reimbursement, ecosystem to be built around CGT

FDA works by indications and risks involved, Standards and expectations for streamlining manufacturing, understanding of process and products 

payments over time payers and Innovators relations Moderator: Julian Harris, MD

  • Partner, Deerfield

Promise of CGT realized, what part?

FDA role and interaction in CGT

Manufacturing aspects which is critical Speaker: Dave Lennon, PhD

  • President, Novartis Gene Therapies

Hope that CGT emerging, how the therapies work, neuro, muscular, ocular, genetic diseases of liver and of heart revolution for the industry 900 IND application 25 approvals Economic driver Skilled works, VC disease. Modality one time intervention, long duration of impart, reimbursement, ecosystem to be built around CGT

FDA works by indications and risks involved, Standards and expectations for streamlining manufacturing, understanding of process and products 

payments over time payers and Innovators relations

  • Q&A 8:55 AM – 9:10 AM  

8:55 AM – 9:20 AM

The Patient and GCT

GCT development for rare diseases is driven by patient and patient-advocate communities. Understanding their needs and perspectives enables biomarker research, the development of value-driving clinical trial endpoints and successful clinical trials. Industry works with patient communities that help identify unmet needs and collaborate with researchers to conduct disease natural history studies that inform the development of biomarkers and trial endpoints. This panel includes patients who have received cutting-edge GCT therapy as well as caregivers and patient advocates. Moderator: Patricia Musolino, MD, PhD

  • Co-Director Pediatric Stroke and Cerebrovascular Program, MGH
  • Assistant Professor of Neurology, HMS

What is the Power of One – the impact that a patient can have on their own destiny by participating in Clinical Trials Contacting other participants in same trial can be beneficial Speakers: Jack Hogan

  • Patient, MEE

Jeanette Hogan

  • Parent of Patient, MEE

Jim Holland

  • CEO, Backcountry.com

Parkinson patient Constraints by regulatory on participation in clinical trial advance stage is approved participation Patients to determine the level of risk they wish to take Information dissemination is critical Barbara Lavery

  • Chief Program Officer, ACGT Foundation

Advocacy agency beginning of work Global Genes educational content and out reach to access the information 

Patient has the knowledge of the symptoms and recording all input needed for diagnosis by multiple clinicians Early application for CGTDan Tesler

  • Clinical Trial Patient, BWH/DFCC

Experimental Drug clinical trial patient participation in clinical trial is very important to advance the state of scienceSarah Beth Thomas, RN

  • Professional Development Manager, BWH

Outcome is unknown, hope for good, support with resources all advocacy groups, 

  • Q&A 9:25 AM – 9:40 AM  

9:25 AM – 9:45 AM FIRESIDE

GCT Regulatory Framework | Why Different?

  Moderator: Vicki Sato, PhD

  • Chairman of the Board, Vir Biotechnology

Diversity of approaches

Process at FDA generalize from 1st entry to rules more generalizable  Speaker: Peter Marks, MD, PhD

  • Director, Center for Biologics Evaluation and Research, FDA

Last Spring it became clear that something will work a vaccine by June 2020 belief that enough candidates the challenge manufacture enough and scaling up FDA did not predicted the efficacy of mRNA vaccine vs other approaches expected to work

Recover Work load for the pandemic will wean & clear, Gene Therapies IND application remained flat in the face of the pandemic Rare diseases urgency remains Consensus with industry advisory to get input gene therapy Guidance  T-Cell therapy vs Regulation best thinking CGT evolve speedily flexible gained by Guidance

Immune modulators, Immunotherapy Genome editing can make use of viral vectors future technologies nanoparticles and liposome encapsulation 

  • Q&A 9:50 AM – 10:05 AM  

9:50 AM – 10:15 AM

Building a GCT Platform for Mainstream Success

This panel of GCT executives, innovators and investors explore how to best shape a successful GCT strategy. Among the questions to be addressed:

  • How are GCT approaches set around defining and building a platform?
  • Is AAV the leading modality and what are the remaining challenges?
  • What are the alternatives?
  • Is it just a matter of matching modalities to the right indications?

Moderator: Jean-François Formela, MD

  • Partner, Atlas Venture

Established core components of the Platform Speakers: Katherine High, MD

  • President, Therapeutics, AskBio

Three drugs approved in Europe in the Gene therapy space

Regulatory Infrastructure exists for CGT drug approval – as new class of therapeutics

Participants investigators, regulators, patients i. e., MDM 

Hemophilia in male most challenging

Human are natural hosts for AV safety signals Dave Lennon, PhD

  • President, Novartis Gene Therapies

big pharma has portfolios of therapeutics not one drug across Tx areas: cell, gene iodine therapy 

collective learning infrastructure features manufacturing at scale early in development Acquisitions strategy for growth # applications for scaling Rick Modi

  • CEO, Affinia Therapeutics

Copy, paste EDIT from product A to B novel vectors leverage knowledge varient of vector, coder optimization choice of indication is critical exploration on larger populations Speed to R&D and Speed to better gene construct get to clinic with better design vs ASAP 

Data sharing clinical experience with vectors strategies patients selection, vector selection, mitigation, patient type specific Louise Rodino-Klapac, PhD

  • EVP, Chief Scientific Officer, Sarepta Therapeutics

AAV based platform 15 years in development same disease indication vs more than one indication stereotype, analytics as hurdle 1st was 10 years 2nd was 3 years

Safety to clinic vs speed to clinic, difference of vectors to trust

  • Q&A 10:20 AM – 10:35 AM  

10:20 AM – 10:45 AM

AAV Success Studies | Retinal Dystrophy | Spinal Muscular Atrophy

Recent AAV gene therapy product approvals have catalyzed the field. This new class of therapies has shown the potential to bring transformative benefit to patients. With dozens of AAV treatments in clinical studies, all eyes are on the field to gauge its disruptive impact.

The panel assesses the largest challenges of the first two products, the lessons learned for the broader CGT field, and the extent to which they serve as a precedent to broaden the AAV modality.

  • Is AAV gene therapy restricted to genetically defined disorders, or will it be able to address common diseases in the near term?
  • Lessons learned from these first-in-class approvals.
  • Challenges to broaden this modality to similar indications.
  • Reflections on safety signals in the clinical studies?

Moderator: Joan Miller, MD

  • Chief, Ophthalmology, MEE
  • Cogan Professor & Chair of Ophthalmology, HMS

Retina specialist, Luxturna success FMA condition cell therapy as solution

Lessons learned

Safety Speakers: Ken Mills

  • CEO, RegenXBio

Tissue types additional administrations, tech and science, address additional diseases, more science for photoreceptors a different tissue type underlying pathology novelties in last 10 years 

Cell therapy vs transplant therapy no immunosuppressionEric Pierce, MD, PhD

  • Director, Ocular Genomics Institute, MEE
  • Professor of Ophthalmology, HMS

Laxterna success to be replicated platform, paradigms measurement visual improved

More science is needed to continue develop vectors reduce toxicity,

AAV can deliver different cargos reduce adverse events improve vectorsRon Philip

  • Chief Operating Officer, Spark Therapeutics

The first retinal gene therapy, voretigene neparvovec-rzyl (Luxturna, Spark Therapeutics), was approved by the FDA in 2017.Meredith Schultz, MD

  • Executive Medical Director, Lead TME, Novartis Gene Therapies

Impact of cell therapy beyond muscular dystrophy, translational medicine, each indication, each disease, each group of patients build platform unlock the promise

Monitoring for Safety signals real world evidence remote markers, home visits, clinical trial made safer, better communication of information

  • Q&A 10:50 AM – 11:05 AM  

10:45 AM – 10:55 AM

Break

  10:55 AM – 11:05 AM FIRST LOOK

Control of AAV pharmacology by Rational Capsid Design

Luk Vandenberghe, PhD

  • Grousbeck Family Chair, Gene Therapy, MEE
  • Associate Professor, Ophthalmology, HMS

AAV a complex driver in Pharmacology durable, vector of choice, administer in vitro, gene editing tissue specificity, pharmacokinetics side effects and adverse events manufacturability site variation diversify portfolios,

Pathway for rational AAV rational design, curated smart variant libraries, AAV  sequence screen multiparametric , data enable liver (de-) targeting unlock therapeutics areas: cochlea 

  • Q&A 11:05 AM – 11:25 AM  

11:05 AM – 11:15 AM FIRST LOOK

Enhanced gene delivery and immunoevasion of AAV vectors without capsid modification

Casey Maguire, PhD

  • Associate Professor of Neurology, MGH & HMS

Virus Biology: Enveloped (e) or not 

enveloped for gene therapy eAAV platform technology: tissue targets and Indications commercialization of eAAV 

  • Q&A 11:15 AM – 11:35 AM  

11:20 AM – 11:45 AM HOT TOPICS

AAV Delivery

This panel will address the advances in the area of AAV gene therapy delivery looking out the next five years. Questions that loom large are: How can biodistribution of AAV be improved? What solutions are in the wings to address immunogenicity of AAV? Will patients be able to receive systemic redosing of AAV-based gene therapies in the future? What technical advances are there for payload size? Will the cost of manufacturing ever become affordable for ultra-rare conditions? Will non-viral delivery completely supplant viral delivery within the next five years?What are the safety concerns and how will they be addressed? Moderators: Xandra Breakefield, PhD

  • Geneticist, MGH, MGH
  • Professor, Neurology, HMS

Florian Eichler, MD

  • Director, Center for Rare Neurological Diseases, MGH
  • Associate Professor, Neurology, HMS

Speakers: Jennifer Farmer

  • CEO, Friedreich’s Ataxia Research Alliance

Ataxia requires therapy targeting multiple organ with one therapy, brain, spinal cord, heart several IND, clinical trials in 2022Mathew Pletcher, PhD

  • SVP, Head of Gene Therapy Research and Technical Operations, Astellas

Work with diseases poorly understood, collaborations needs example of existing: DMD is a great example explain dystrophin share placedo data 

Continue to explore large animal guinea pig not the mice, not primates (ethical issues) for understanding immunogenicity and immune response Manny Simons, PhD

  • CEO, Akouos

AAV Therapy for the fluid of the inner ear, CGT for the ear vector accessible to surgeons translational work on the inner ear for gene therapy right animal model 

Biology across species nerve ending in the cochlea

engineer out of the caspid, lowest dose possible, get desired effect by vector use, 2022 new milestones

  • Q&A 11:50 AM – 12:05 PM  

11:50 AM – 12:15 PM

M&A | Shaping GCT Innovation

The GCT M&A market is booming – many large pharmas have made at least one significant acquisition. How should we view the current GCT M&A market? What is its impact of the current M&A market on technology development? Are these M&A trends new are just another cycle? Has pharma strategy shifted and, if so, what does it mean for GCT companies? What does it mean for patients? What are the long-term prospects – can valuations hold up? Moderator: Adam Koppel, MD, PhD

  • Managing Director, Bain Capital Life Sciences

What acquirers are looking for??

What is the next generation vs what is real where is the industry going? Speakers:

Debby Baron,

  • Worldwide Business Development, Pfizer 

CGT is an important area Pfizer is active looking for innovators, advancing forward programs of innovation with the experience Pfizer has internally 

Scalability and manufacturing  regulatory conversations, clinical programs safety in parallel to planning getting drug to patients

Kenneth Custer, PhD

  • Vice President, Business Development and Lilly New Ventures, Eli Lilly and Company

Marianne De Backer, PhD

Head of Strategy, Business Development & Licensing, and Member of the Executive Committee, Bayer

Absolute Leadership in Gene editing, gene therapy, via acquisition and strategic alliance 

Operating model of the acquired company discussed , company continue independence

Sean Nolan

  • Board Chairman, Encoded Therapeutics & Affinia

Executive Chairman, Jaguar Gene Therapy & Istari Oncology

As acquiree multiple M&A: How the acquirer looks at integration and cultures of the two companies 

Traditional integration vs jump start by external acquisition 

AAV – epilepsy, next generation of vectors 

  • Q&A 12:20 PM – 12:35 PM  

12:15 PM – 12:25 PM FIRST LOOK

Gene Therapies for Neurological Disorders: Insights from Motor Neuron Disorders

Merit Cudkowicz, MD

  • Chief of Neurology, MGH

ALS – Man 1in 300, Women 1 in 400, next decade increase 7% 

10% ALS is heredity 160 pharma in ALS space, diagnosis is late 1/3 of people are not diagnosed, active community for clinical trials Challenges: disease heterogeneity cases of 10 years late in diagnosis. Clinical Trials for ALS in Gene Therapy targeting ASO1 protein therapies FUS gene struck youngsters 

Q&A

  • 12:25 PM – 12:45 PM  

12:25 PM – 12:35 PM FIRST LOOK

Gene Therapy for Neurologic Diseases

Patricia Musolino, MD, PhD

  • Co-Director Pediatric Stroke and Cerebrovascular Program, MGH
  • Assistant Professor of Neurology, HMS

Cerebral Vascular disease – ACTA2 179H gene smooth muscle cell proliferation disorder

no surgery or drug exist –

Cell therapy for ACTA2 Vasculopathy  in the brain and control the BP and stroke – smooth muscle intima proliferation. Viral vector deliver aiming to change platform to non-viral delivery rare disease , gene editing, other mutations of ACTA2 gene target other pathway for atherosclerosis 

  • Q&A 12:35 PM – 12:55 PM  

12:35 PM – 1:15 PM

Lunch

  1:15 PM – 1:40 PM

Oncolytic Viruses in Cancer | Curing Melanoma and Beyond

Oncolytic viruses represent a powerful new technology, but so far an FDA-approved oncolytic (Imlygic) has only occurred in one area – melanoma and that what is in 2015. This panel involves some of the protagonists of this early success story.  They will explore why and how Imlygic became approved and its path to commercialization.  Yet, no other cancer indications exist for Imlygic, unlike the expansion of FDA-approved indication for immune checkpoint inhibitors to multiple cancers.  Why? Is there a limitation to what and which cancers can target?  Is the mode of administration a problem?

No other oncolytic virus therapy has been approved since 2015. Where will the next success story come from and why?  Will these therapies only be beneficial for skin cancers or other easily accessible cancers based on intratumoral delivery?

The panel will examine whether the preclinical models that have been developed for other cancer treatment modalities will be useful for oncolytic viruses.  It will also assess the extent pre-clinical development challenges have slowed the development of OVs. Moderator: Nino Chiocca, MD, PhD

  • Neurosurgeon-in-Chief and Chairman, Neurosurgery, BWH
  • Harvey W. Cushing Professor of Neurosurgery, HMS

Challenges of manufacturing at Amgen what are they? Speakers: Robert Coffin, PhD

  • Chief Research & Development Officer, Replimune

2002 in UK promise in oncolytic therapy GNCSF

Phase III melanoma 2015 M&A with Amgen

oncolytic therapy remains non effecting on immune response 

data is key for commercialization 

do not belief in systemic therapy achieve maximum immune response possible from a tumor by localized injection Roger Perlmutter, MD, PhD

  • Chairman, Merck & Co.

response rates systemic therapy like PD1, Keytruda, OPTIVA well tolerated combination of Oncolytic with systemic 

GMP critical for manufacturing David Reese, MD

  • Executive Vice President, Research and Development, Amgen

Inter lesion injection of agent vs systemic therapeutics 

cold tumors immune resistant render them immune susceptible 

Oncolytic virus is a Mono therapy

addressing the unknown Ann Silk, MD

  • Physician, Dana Farber-Brigham and Women’s Cancer Center
  • Assistant Professor of Medicine, HMS

Which person gets oncolytics virus if patient has immune suppression due to other indications

Safety of oncolytic virus greater than Systemic treatment

series biopsies for injected and non injected tissue and compare Suspect of hot tumor and cold tumors likely to have sme response to agent unknown all potential 

  • Q&A 1:45 PM – 2:00 PM  

1:45 PM – 2:10 PM

Market Interest in Oncolytic Viruses | Calibrating

There are currently two oncolytic virus products on the market, one in the USA and one in China.  As of late 2020, there were 86 clinical trials 60 of which were in phase I with just 2 in Phase III the rest in Phase I/II or Phase II.   Although global sales of OVs are still in the ramp-up phase, some projections forecast OVs will be a $700 million market by 2026. This panel will address some of the major questions in this area:

What regulatory challenges will keep OVs from realizing their potential? Despite the promise of OVs for treating cancer only one has been approved in the US. Why has this been the case? Reasons such have viral tropism, viral species selection and delivery challenges have all been cited. However, these are also true of other modalities. Why then have oncolytic virus approaches not advanced faster and what are the primary challenges to be overcome?

  • Will these need to be combined with other agents to realize their full efficacy and how will that impact the market?
  • Why are these companies pursuing OVs while several others are taking a pass?

Moderators: Martine Lamfers, PhD

  • Visiting Scientist, BWH

Challenged in development of strategies 

Demonstrate efficacyRobert Martuza, MD

  • Consultant in Neurosurgery, MGH
  • William and Elizabeth Sweet Distinguished Professor of Neurosurgery, HMS

Modulation mechanism Speakers: Anlong Li, MD, PhD

  • Clinical Director, Oncology Clinical Development, Merck Research Laboratories

IV delivery preferred – delivery alternative are less aggereable Jeffrey Infante, MD

  • Early development Oncolytic viruses, Oncology, Janssen Research & Development

oncologic virus if it will generate systemic effects the adoption will accelerate

What areas are the best efficacious 

Direct effect with intra-tumor single injection with right payload 

Platform approach  Prime with 1 and Boost with 2 – not yet experimented with 

Do not have the data at trial design for stratification of patients 

Turn off strategy not existing yetLoic Vincent, PhD

  • Head of Oncology Drug Discovery Unit, Takeda

R&D in collaboration with Academic

Vaccine platform to explore different payload

IV administration may not bring sufficient concentration to the tumor is administer  in the blood stream

Classification of Patients by prospective response type id UNKNOWN yet, population of patients require stratification

  • Q&A 2:15 PM – 2:30 PM  

2:10 PM – 2:20 PM FIRST LOOK

Oncolytic viruses: turning pathogens into anticancer agents

Nino Chiocca, MD, PhD

  • Neurosurgeon-in-Chief and Chairman, Neurosurgery, BWH
  • Harvey W. Cushing Professor of Neurosurgery, HMS

Oncolytic therapy DID NOT WORK Pancreatic Cancer and Glioblastoma 

Intra- tumoral heterogeniety hinders success 

Solution: Oncolytic VIRUSES – Immunological “coldness”

GADD-34 20,000 GBM 40,000 pancreatic cancer

  • Q&A 2:25 PM – 2:40 PM  

2:20 PM – 2:45 PM

Entrepreneurial Growth | Oncolytic Virus

In 2020 there were a total of 60 phase I trials for Oncolytic Viruses. There are now dozens of companies pursuing some aspect of OV technology. This panel will address:

  •  How are small companies equipped to address the challenges of developing OV therapies better than large pharma or biotech?
  • Will the success of COVID vaccines based on Adenovirus help the regulatory environment for small companies developing OV products in Europe and the USA?
  • Is there a place for non-viral delivery and other immunotherapy companies to engage in the OV space?  Would they bring any real advantages?

Moderator: Reid Huber, PhD

  • Partner, Third Rock Ventures

Critical milestones to observe Speakers: Caroline Breitbach, PhD

  • VP, R&D Programs and Strategy, Turnstone Biologics

Trying Intra-tumor delivery and IV infusion delivery oncolytic vaccine pushing dose 

translation biomarkers program 

transformation tumor microenvironment Brett Ewald, PhD

  • SVP, Development & Corporate Strategy, DNAtrix

Studies gets larger, kicking off Phase III multiple tumors Paul Hallenbeck, PhD

  • President and Chief Scientific Officer, Seneca Therapeutics

Translation: Stephen Russell, MD, PhD

  • CEO, Vyriad

Systemic delivery Oncolytic Virus IV delivery woman in remission

Collaboration with Regeneron

Data collection: Imageable reporter secretable reporter, gene expression

Field is intense systemic oncolytic delivery is exciting in mice and in human, response rates are encouraging combination immune stimulant, check inhibitors 

  • Q&A 2:50 PM – 3:05 PM  

2:45 PM – 3:00 PM

Break

  3:00 PM – 3:25 PM

CAR-T | Lessons Learned | What’s Next

Few areas of potential cancer therapy have had the attention and excitement of CAR-T. This panel of leading executives, developers, and clinician-scientists will explore the current state of CAR-T and its future prospects. Among the questions to be addressed are:

  • Is CAR-T still an industry priority – i.e. are new investments being made by large companies? Are new companies being financed? What are the trends?
  • What have we learned from first-generation products, what can we expect from CAR-T going forward in novel targets, combinations, armored CAR’s and allogeneic treatment adoption?
  • Early trials showed remarkable overall survival and progression-free survival. What has been observed regarding how enduring these responses are?
  • Most of the approvals to date have targeted CD19, and most recently BCMA. What are the most common forms of relapses that have been observed?
  • Is there a consensus about what comes after these CD19 and BCMA trials as to additional targets in liquid tumors? How have dual-targeted approaches fared?
  • Moderator:
  • Marcela Maus, MD, PhD
    • Director, Cellular Immunotherapy Program, Cancer Center, MGH
    • Associate Professor, Medicine, HMSIs CAR-T Industry priority
  • Speakers:
  • Head of R&D, Atara BioTherapeutics
  • Phyno-type of the cells for hematologic cancers 
  • solid tumor 
  • inventory of Therapeutics for treating patients in the future 
  • Progressive MS program
  • EBBT platform B-Cells and T-Cells
    • Stefan Hendriks
      • Gobal Head, Cell & Gene, Novartis
      • yes, CGT is a strategy in the present and future
      • Journey started years ago 
      • Confirmation the effectiveness of CAR-T therapies, 1 year response prolonged to 5 years 26 months
      • Patient not responding – a lot to learn
      • Patient after 8 months of chemo can be helped by CAR-T
    • Christi Shaw
      • CEO, Kite
      • CAR-T is priority 120 companies in the space
      • Manufacturing consistency 
      • Patients respond with better quality of life
      • Blood cancer – more work to be done

Q&A

  • 3:30 PM – 3:45 PM  

3:30 PM – 3:55 PM HOT TOPICS

CAR-T | Solid Tumors Success | When?

The potential application of CAR-T in solid tumors will be a game-changer if it occurs. The panel explores the prospects of solid tumor success and what the barriers have been. Questions include:

  •  How would industry and investor strategy for CAR-T and solid tumors be characterized? Has it changed in the last couple of years?
  •  Does the lack of tumor antigen specificity in solid tumors mean that lessons from liquid tumor CAR-T constructs will not translate well and we have to start over?
  •  Whether due to antigen heterogeneity, a hostile tumor micro-environment, or other factors are some specific solid tumors more attractive opportunities than others for CAR-T therapy development?
  •  Given the many challenges that CAR-T faces in solid tumors, does the use of combination therapies from the start, for example, to mitigate TME effects, offer a more compelling opportunity.

Moderator: Oladapo Yeku, MD, PhD

  • Clinical Assistant in Medicine, MGH

window of opportunities studies  Speakers: Jennifer Brogdon

  • Executive Director, Head of Cell Therapy Research, Exploratory Immuno-Oncology, NIBR

2017 CAR-T first approval

M&A and research collaborations

TCR tumor specific antigens avoid tissue toxicity Knut Niss, PhD

  • CTO, Mustang Bio

tumor hot start in 12 month clinical trial solid tumors , theraties not ready yet. Combination therapy will be an experimental treatment long journey checkpoint inhibitors to be used in combination maintenance Lipid tumor Barbra Sasu, PhD

  • CSO, Allogene

T cell response at prostate cancer 

tumor specific 

cytokine tumor specific signals move from solid to metastatic cell type for easier infiltration

Where we might go: safety autologous and allogeneic Jay Short, PhD

  • Chairman, CEO, Cofounder, BioAlta, Inc.

Tumor type is not enough for development of therapeutics other organs are involved in the periphery

difficult to penetrate solid tumors biologics activated in the tumor only, positive changes surrounding all charges, water molecules inside the tissue acidic environment target the cells inside the tumor and not outside 

Combination staggered key is try combination

  • Q&A 4:00 PM – 4:15 PM  

4:00 PM – 4:25 PM

GCT Manufacturing | Vector Production | Autologous and Allogeneic | Stem Cells | Supply Chain | Scalability & Management

The modes of GCT manufacturing have the potential of fundamentally reordering long-established roles and pathways. While complexity goes up the distance from discovery to deployment shrinks. With the likelihood of a total market for cell therapies to be over $48 billion by 2027,  groups of products are emerging.  Stem cell therapies are projected to be $28 billion by 2027 and non-stem cell therapies such as CAR-T are projected be $20 billion by 2027. The manufacturing challenges for these two large buckets are very different. Within the CAR-T realm there are diverging trends of autologous and allogeneic therapies and the demands on manufacturing infrastructure are very different. Questions for the panelists are:

  • Help us all understand the different manufacturing challenges for cell therapies. What are the trade-offs among storage cost, batch size, line changes in terms of production cost and what is the current state of scaling naïve and stem cell therapy treatment vs engineered cell therapies?
  • For cell and gene therapy what is the cost of Quality Assurance/Quality Control vs. production and how do you think this will trend over time based on your perspective on learning curves today?
  • Will point of care production become a reality? How will that change product development strategy for pharma and venture investors? What would be the regulatory implications for such products?
  • How close are allogeneic CAR-T cell therapies? If successful what are the market implications of allogenic CAR-T? What are the cost implications and rewards for developing allogeneic cell therapy treatments?

Moderator: Michael Paglia

  • VP, ElevateBio

Speakers:

  • Dannielle Appelhans
    • SVP TechOps and Chief Technical Officer, Novartis Gene Therapies
  • Thomas Page, PhD
    • VP, Engineering and Asset Development, FUJIFILM Diosynth Biotechnologies
  • Rahul Singhvi, ScD
    • CEO and Co-Founder, National Resilience, Inc.
  • Thomas VanCott, PhD
    • Global Head of Product Development, Gene & Cell Therapy, Catalent
    • 2/3 autologous 1/3 allogeneic  CAR-T high doses and high populations scale up is not done today quality maintain required the timing logistics issues centralized vs decentralized  allogeneic are health donors innovations in cell types in use improvements in manufacturing

Ropa Pike, Director,  Enterprise Science & Partnerships, Thermo Fisher Scientific 

Centralized biopharma industry is moving  to decentralized models site specific license 

  • Q&A 4:30 PM – 4:45 PM  

4:30 PM – 4:40 PM FIRST LOOK

CAR-T

Marcela Maus, MD, PhD

  • Director, Cellular Immunotherapy Program, Cancer Center, MGH
  • Assistant Professor, Medicine, HMS 

Fit-to-purpose CAR-T cells: 3 lead programs

Tr-fill 

CAR-T induce response myeloma and multiple myeloma GBM

27 patents on CAR-T

+400 patients treaded 40 Clinical Trials 

  • Q&A 4:40 PM – 5:00 PM  

4:40 PM – 4:50 PM FIRST LOOK

Repurposed Tumor Cells as Killers and Immunomodulators for Cancer Therapy

Khalid Shah, PhD

  • Vice Chair, Neurosurgery Research, BWH
  • Director, Center for Stem Cell Therapeutics and Imaging, HMS

Solid tumors are the hardest to treat because: immunosuppressive, hypoxic, Acidic Use of autologous tumor cells self homing ThTC self targeting therapeutic cells Therapeutic tumor cells efficacy pre-clinical models GBM 95% metastesis ThTC translation to patient settings

  • Q&A 4:50 PM – 5:10 PM  

4:50 PM – 5:00 PM FIRST LOOK

Other Cell Therapies for Cancer

David Scadden, MD

  • Director, Center for Regenerative Medicine; Co-Director, Harvard Stem Cell Institute, Director, Hematologic Malignancies & Experimental Hematology, MGH
  • Jordan Professor of Medicine, HMS

T-cell are made in bone marrow create cryogel  can be an off-the-shelf product repertoire on T Receptor CCL19+ mesenchymal cells mimic Tymus cells –

inter-tymic injection. Non human primate validation

Q&A

 

5:00 PM – 5:20 PM   5:00 PM – 5:20 PM FIRESIDE

Fireside with Mikael Dolsten, MD, PhD

  Introducer: Jonathan Kraft Moderator: Daniel Haber, MD, PhD

  • Chair, Cancer Center, MGH
  • Isselbacher Professor of Oncology, HMS

Vaccine Status Mikael Dolsten, MD, PhD

  • Chief Scientific Officer and President, Worldwide Research, Development and Medical, Pfizer

Deliver vaccine around the Globe, Israel, US, Europe.

3BIL vaccine in 2022 for all Global vaccination 

Bio Ntech in Germany

Experience with Biologics immuneoncology & allogeneic antibody cells – new field for drug discovery 

mRNA curative effort and cancer vaccine 

Access to drugs developed by Pfizer to underdeveloped countries 

  • Q&A 5:25 PM – 5:40 AM  

5:20 PM – 5:30 PM

Closing Remarks

Thursday, May 20, 2021

8:00 AM – 8:25 AM

GCT | The China Juggernaut

China embraced gene and cell therapies early. The first China gene therapy clinical trial was in 1991. China approved the world’s first gene therapy product in 2003—Gendicine—an oncolytic adenovirus for the treatment of advanced head and neck cancer.  Driven by broad national strategy, China has become a hotbed of GCT development, ranking second in the world with more than 1,000 clinical trials either conducted or underway and thousands of related patents.  It has a booming GCT biotech sector, led by more than 45 local companies with growing IND pipelines.

In late 1990, a T cell-based immunotherapy, cytokine-induced killer (CIK) therapy became a popular modality in the clinic in China for tumor treatment.  In early 2010, Chinese researchers started to carry out domestic CAR T trials inspired by several important reports suggested the great antitumor function of CAR T cells. Now, China became the country with the most registered CAR T trials, CAR T therapy is flourishing in China.

The Chinese GCT ecosystem has increasingly rich local innovation and growing complement of development and investment partnerships – and also many subtleties.

This panel, consisting of leaders from the China GCT corporate, investor, research and entrepreneurial communities, will consider strategic questions on the growth of the gene and cell therapy industry in China, areas of greatest strength, evolving regulatory framework, early successes and products expected to reach the US and world market. Moderator: Min Wu, PhD

  • Managing Director, Fosun Health Fund

What are the area of CGT in China, regulatory similar to the US Speakers: Alvin Luk, PhD

  • CEO, Neuropath Therapeutics

Monogenic rare disease with clear genomic target

Increase of 30% in patient enrollment 

Regulatory reform approval is 60 days no delayPin Wang, PhD

  • CSO, Jiangsu Simcere Pharmaceutical Co., Ltd.

Similar starting point in CGT as the rest of the World unlike a later starting point in other biologicalRichard Wang, PhD

  • CEO, Fosun Kite Biotechnology Co., Ltd

Possibilities to be creative and capitalize the new technologies for innovating drug

Support of the ecosystem by funding new companie allowing the industry to be developed in China

Autologous in patients differences cost challengeTian Xu, PhD

  • Vice President, Westlake University

ICH committee and Chinese FDA -r regulation similar to the US

Difference is the population recruitment, in China patients are active participants in skin disease 

Active in development of transposome 

Development of non-viral methods, CRISPR still in D and transposome

In China price of drugs regulatory are sensitive Shunfei Yan, PhD

  • Investment Manager, InnoStar Capital

Indication driven: Hymophilia, 

Allogogenic efficiency therapies

Licensing opportunities 

  • Q&A 8:30 AM – 8:45 AM  

8:30 AM – 8:55 AM

Impact of mRNA Vaccines | Global Success Lessons

The COVID vaccine race has propelled mRNA to the forefront of biomedicine. Long considered as a compelling modality for therapeutic gene transfer, the technology may have found its most impactful application as a vaccine platform. Given the transformative industrialization, the massive human experience, and the fast development that has taken place in this industry, where is the horizon? Does the success of the vaccine application, benefit or limit its use as a therapeutic for CGT?

  • How will the COVID success impact the rest of the industry both in therapeutic and prophylactic vaccines and broader mRNA lessons?
  • How will the COVID success impact the rest of the industry both on therapeutic and prophylactic vaccines and broader mRNA lessons?
  • Beyond from speed of development, what aspects make mRNA so well suited as a vaccine platform?
  • Will cost-of-goods be reduced as the industry matures?
  • How does mRNA technology seek to compete with AAV and other gene therapy approaches?

Moderator: Lindsey Baden, MD

  • Director, Clinical Research, Division of Infectious Diseases, BWH
  • Associate Professor, HMS

In vivo delivery process regulatory cooperation new opportunities for same platform for new indication Speakers:

Many years of mRNA pivoting for new diseases, DARPA, nucleic Acids global deployment of a manufacturing unit on site where the need arise Elan Musk funds new directions at Moderna

How many mRNA can be put in one vaccine: Dose and tolerance to achieve efficacy 

45 days for Personalized cancer vaccine one per patient

1.6 Billion doses produced rare disease monogenic correct mRNA like CF multiple mutation infection disease and oncology applications

Platform allowing to swap cargo reusing same nanoparticles address disease beyond Big Pharma options for biotech

WHat strain of Flu vaccine will come back in the future when people do not use masks 

  • Kate Bingham, UK Vaccine Taskforce

July 2020, AAV vs mRNA delivery across UK local centers administered both types supply and delivery uplift 

  • Q&A 9:00 AM – 9:15 AM  

9:00 AM – 9:25 AM HOT TOPICS

Benign Blood Disorders

Hemophilia has been and remains a hallmark indication for the CGT. Given its well-defined biology, larger market, and limited need for gene transfer to provide therapeutic benefit, it has been at the forefront of clinical development for years, however, product approval remains elusive. What are the main hurdles to this success? Contrary to many indications that CGT pursues no therapeutic options are available to patients, hemophiliacs have an increasing number of highly efficacious treatment options. How does the competitive landscape impact this field differently than other CGT fields? With many different players pursuing a gene therapy option for hemophilia, what are the main differentiators? Gene therapy for hemophilia seems compelling for low and middle-income countries, given the cost of currently available treatments; does your company see opportunities in this market? Moderator: Nancy Berliner, MD

  • Chief, Division of Hematology, BWH
  • H. Franklin Bunn Professor of Medicine, HMS

Speakers: Theresa Heggie

  • CEO, Freeline Therapeutics

Safety concerns, high burden of treatment CGT has record of safety and risk/benefit adoption of Tx functional cure CGT is potent Tx relative small quantity of protein needs be delivered 

Potency and quality less quantity drug and greater potency

risk of delivery unwanted DNA, capsules are critical 

analytics is critical regulator involvement in potency definition

Close of collaboration is excitingGallia Levy, MD, PhD

  • Chief Medical Officer, Spark Therapeutics

Hemophilia CGT is the highest potential for Global access logistics in underdeveloped countries working with NGOs practicality of the Tx

Roche reached 120 Counties great to be part of the Roche GroupAmir Nashat, PhD

  • Managing Partner, Polaris Ventures

Suneet Varma

  • Global President of Rare Disease, Pfizer

Gene therapy at Pfizer small molecule, large molecule and CGT – spectrum of choice allowing Hemophilia patients to marry 

1/3 internal 1/3 partnership 1/3 acquisitions 

Learning from COVID-19 is applied for other vaccine development

review of protocols and CGT for Hemophelia

You can’t buy Time

With MIT Pfizer is developing a model for Hemopilia CGT treatment

  • Q&A 9:30 AM – 9:45 AM  

9:25 AM – 9:35 AM FIRST LOOK

Treating Rett Syndrome through X-reactivation

Jeannie Lee, MD, PhD

  • Molecular Biologist, MGH
  • Professor of Genetics, HMS

200 disease X chromosome unlock for neurological genetic diseases: Rett Syndromeand other autism spectrum disorders female model vs male mice model

deliver protein to the brain 

restore own missing or dysfunctional protein

Epigenetic not CGT – no exogent intervention Xist ASO drug

Female model

  • Q&A 9:35 AM – 9:55 AM  

9:35 AM – 9:45 AM FIRST LOOK

Rare but mighty: scaling up success in single gene disorders

Florian Eichler, MD

  • Director, Center for Rare Neurological Diseases, MGH
  • Associate Professor, Neurology, HMS

Single gene disorder NGS enable diagnosis, DIagnosis to Treatment How to know whar cell to target, make it available and scale up Address gap: missing components Biomarkers to cell types lipid chemistry cell animal biology 

crosswalk from bone marrow matter 

New gene discovered that causes neurodevelopment of stagnant genes Examining new Biology cell type specific biomarkers 

  • Q&A 9:45 AM – 10:05 AM  

9:50 AM – 10:15 AM HOT TOPICS

Diabetes | Grand Challenge

The American Diabetes Association estimates 30 million Americans have diabetes and 1.5 million are diagnosed annually. GCT offers the prospect of long-sought treatment for this enormous cohort and their chronic requirements. The complexity of the disease and its management constitute a grand challenge and highlight both the potential of GCT and its current limitations.

  •  Islet transplantation for type 1 diabetes has been attempted for decades. Problems like loss of transplanted islet cells due to autoimmunity and graft site factors have been difficult to address. Is there anything different on the horizon for gene and cell therapies to help this be successful?
  • How is the durability of response for gene or cell therapies for diabetes being addressed? For example, what would the profile of an acceptable (vs. optimal) cell therapy look like?

Moderator: Marie McDonnell, MD

  • Chief, Diabetes Section and Director, Diabetes Program, BWH
  • Lecturer on Medicine, HMS

Type 1 Diabetes cost of insulin for continuous delivery of drug

alternative treatments: 

The Future: neuropotent stem cells 

What keeps you up at night  Speakers: Tom Bollenbach, PhD

  • Chief Technology Officer, Advanced Regenerative Manufacturing Institute

Data managment sterility sensors, cell survival after implantation, stem cells manufacturing, process development in manufacturing of complex cells

Data and instrumentation the Process is the Product

Manufacturing tight schedules Manasi Jaiman, MD

  • Vice President, Clinical Development, ViaCyte
  • Pediatric Endocrinologist

continous glucose monitoring Bastiano Sanna, PhD

  • EVP, Chief of Cell & Gene Therapies and VCGT Site Head, Vertex Pharmaceuticals

100 years from discovering Insulin, Insulin is not a cure in 2021 – asking patients to partner more 

Produce large quantities of the Islet cells encapsulation technology been developed 

Scaling up is a challengeRogerio Vivaldi, MD

  • CEO, Sigilon Therapeutics

Advanced made, Patient of Type 1 Outer and Inner compartments of spheres (not capsule) no immune suppression continuous secretion of enzyme Insulin independence without immune suppression 

Volume to have of-the-shelf inventory oxegenation in location lymphatic and vascularization conrol the whole process modular platform learning from others

  • Q&A 10:20 AM – 10:35 AM  

10:20 AM – 10:40 AM FIRESIDE

Building A Unified GCT Strategy

  Introducer: John Fish

  • CEO, Suffolk
  • Chairman of Board Trustees, Brigham Health

Moderator: Meg Tirrell

  • Senior Health and Science Reporter, CNBC

Last year, what was it at Novartis Speaker: Jay Bradner, MD

  • President, NIBR

Keep eyes open, waiting the Pandemic to end and enable working back on all the indications 

Portfolio of MET, Mimi Emerging Therapies 

Learning from the Pandemic – operationalize the practice science, R&D leaders, new collaboratives at NIH, FDA, Novartis

Pursue programs that will yield growth, tropic diseases with Gates Foundation, Rising Tide pods for access CGT within Novartis Partnership with UPenn in Cell Therapy 

Cost to access to IP from Academia to a Biotech CRISPR accessing few translations to Clinic

Protein degradation organization constraint valuation by parties in a partnership 

Novartis: nuclear protein lipid nuclear particles, tamplate for Biotech to collaborate

Game changing: 10% of the Portfolio, New frontiers human genetics in Ophthalmology, CAR-T, CRISPR, Gene Therapy Neurological and payloads of different matter

  • Q&A 10:45 AM – 11:00 AM  

10:40 AM – 10:50 AM

Break

  10:50 AM – 11:00 AM FIRST LOOK

Getting to the Heart of the Matter: Curing Genetic Cardiomyopathy

Christine Seidman, MD

  • Director, Cardiovascular Genetics Center, BWH
  • Smith Professor of Medicine & Genetics, HMS

The Voice of Dr. Seidman – Her abstract is cited below

The ultimate opportunity presented by discovering the genetic basis of human disease is accurate prediction and disease prevention. To enable this achievement, genetic insights must enable the identification of at-risk

individuals prior to end-stage disease manifestations and strategies that delay or prevent clinical expression. Genetic cardiomyopathies provide a paradigm for fulfilling these opportunities. Hypertrophic cardiomyopathy (HCM) is characterized by left ventricular hypertrophy, diastolic dysfunction with normal or enhanced systolic performance and a unique histopathology: myocyte hypertrophy, disarray and fibrosis. Dilated cardiomyopathy (DCM) exhibits enlarged ventricular volumes with depressed systolic performance and nonspecific histopathology. Both HCM and DCM are prevalent clinical conditions that increase risk for arrhythmias, sudden death, and heart failure. Today treatments for HCM and DCM focus on symptoms, but none prevent disease progression. Human molecular genetic studies demonstrated that these pathologies often result from dominant mutations in genes that encode protein components of the sarcomere, the contractile unit in striated muscles. These data combined with the emergence of molecular strategies to specifically modulate gene expression provide unparalleled opportunities to silence or correct mutant genes and to boost healthy gene expression in patients with genetic HCM and DCM. Many challenges remain, but the active and vital efforts of physicians, researchers, and patients are poised to ensure success.

Hypertrophic and Dilated Cardiomyopaies ‘

10% receive heart transplant 12 years survival 

Mutation puterb function

TTN: contribute 20% of dilated cardiomyopaty

Silence gene 

pleuripotential cells deliver therapies 

  • Q&A 11:00 AM – 11:20 AM  

11:00 AM – 11:10 AM FIRST LOOK

Unlocking the secret lives of proteins in health and disease

Anna Greka, MD, PhD

  • Medicine, BWH
  • Associate Professor, Medicine, HMS

Cyprus Island, kidney disease by mutation causing MUC1 accumulation and death BRD4780 molecule that will clear the misfolding proteins from the kidney organoids: pleuripotent stem cells small molecule developed for applications in the other cell types in brain, eye, gene mutation build mechnism for therapy clinical models transition from Academia to biotech 

Q&A

  • 11:10 AM – 11:30 AM  

11:10 AM – 11:35 AM

Rare and Ultra Rare Diseases | GCT Breaks Through

One of the most innovative segments in all of healthcare is the development of GCT driven therapies for rare and ultra-rare diseases. Driven by a series of insights and tools and funded in part by disease focused foundations, philanthropists and abundant venture funding disease after disease is yielding to new GCT technology. These often become platforms to address more prevalent diseases. The goal of making these breakthroughs routine and affordable is challenged by a range of issues including clinical trial design and pricing.

  • What is driving the interest in rare diseases?
  • What are the biggest barriers to making breakthroughs ‘routine and affordable?’
  • What is the role of retrospective and prospective natural history studies in rare disease?  When does the expected value of retrospective disease history studies justify the cost?
  • Related to the first question, what is the FDA expecting as far as controls in clinical trials for rare diseases?  How does this impact the collection of natural history data?

Moderator: Susan Slaugenhaupt, PhD

  • Scientific Director and Elizabeth G. Riley and Daniel E. Smith Jr., Endowed Chair, Mass General Research Institute
  • Professor, Neurology, HMS

Speakers: Leah Bloom, PhD

  • SVP, External Innovation and Strategic Alliances, Novartis Gene Therapies

Ultra rare (less than 100) vs rare difficulty to recruit patients and to follow up after treatment Bobby Gaspar, MD, PhD

  • CEO, Orchard Therapeutics

Study of rare condition have transfer to other larger diseases – delivery of therapeutics genes, like immune disorders 

Patient testimonials just to hear what a treatment can make Emil Kakkis, MD, PhD

  • CEO, Ultragenyx

Do 100 patient study then have information on natural history to develop a clinical trial Stuart Peltz, PhD

  • CEO, PTC Therapeutics

Rare disease, challenge for FDA approval and after market commercialization follow ups

Justification of cost for Rare disease – demonstration of Change is IP in value patients advocacy is helpful

  • Q&A 11:40 AM – 11:55 AM  

11:40 AM – 12:00 PM FIRESIDE

Partnering Across the GCT Spectrum

  Moderator: Erin Harris

  • Chief Editor, Cell & Gene

Perspective & professional tenure

Partnership in manufacturing what are the recommendations?

Hospital systems: Partnership Challenges  Speaker: Marc Casper

  • CEO, ThermoFisher

25 years in Diagnostics last 20 years at ThermoFisher 

products used in the Lab for CAR-T research and manufacture 

CGT Innovations: FDA will have a high level of approval each year

How move from research to clinical trials to manufacturing Quicker process

Best practices in Partnerships: the root cause if acceleration to market service providers to deliver highest standards

Building capacity by acquisition to avoid the waiting time

Accelerate new products been manufactured 

Collaborations with Academic Medical center i.e., UCSF in CGT joint funding to accelerate CGT to clinics’

Customers are extremely knowledgable, scale the capital investment made investment

150MIL a year to improve the Workflow 

  • Q&A 12:05 PM – 12:20 PM  

12:05 PM – 12:30 PM

  • 12:05 PM – 12:20 PM  

12:05 PM – 12:30 PM

CEO Panel | Anticipating Disruption | Planning for Widespread GCT

The power of GCT to cure disease has the prospect of profoundly improving the lives of patients who respond. Planning for a disruption of this magnitude is complex and challenging as it will change care across the spectrum. Leading chief executives shares perspectives on how the industry will change and how this change should be anticipated. Moderator: Meg Tirrell

  • Senior Health and Science Reporter, CNBC

CGT becoming staple therapy what are the disruptors emerging Speakers: Lisa Dechamps

  • SVP & Chief Business Officer, Novartis Gene Therapies

Reimagine medicine with collaboration at MGH, MDM condition in children 

The Science is there, sustainable processes and systems impact is transformational

Value based pricing, risk sharing Payers and Pharma for one time therapy with life span effect

Collaboration with FDAKieran Murphy

  • CEO, GE Healthcare

Diagnosis of disease to be used in CGT

2021 investment in CAR-T platform 

Investment in several CGT frontier

Investment in AI, ML in system design new technologies 

GE: Scale and Global distributions, sponsor companies in software 

Waste in Industry – Healthcare % of GDP, work with MGH to smooth the workflow faster entry into hospital and out of Hospital

Telemedicine during is Pandemic: Radiologist needs to read remotely 

Supply chain disruptions slow down all ecosystem 

Production of ventilators by collaboration with GM – ingenuity 

Scan patients outside of hospital a scanner in a Box Christian Rommel, PhD

  • Head, Pharmaceuticals Research & Development, Bayer AG

CGT – 2016 and in 2020 new leadership and capability 

Disease Biology and therapeutics

Regenerative Medicine: CGT vs repair building pipeline in ophthalmology and cardiovascular 

During Pandemic: Deliver Medicines like Moderna, Pfizer – collaborations between competitors with Government Bayer entered into Vaccines in 5 days, all processes had to change access innovations developed over decades for medical solutions 

  • Q&A 12:35 PM – 12:50 PM  

12:35 PM – 12:55 PM FIRESIDE

Building a GCT Portfolio

GCT represents a large and growing market for novel therapeutics that has several segments. These include Cardiovascular Disease, Cancer, Neurological Diseases, Infectious Disease, Ophthalmology, Benign Blood Disorders, and many others; Manufacturing and Supply Chain including CDMO’s and CMO’s; Stem Cells and Regenerative Medicine; Tools and Platforms (viral vectors, nano delivery, gene editing, etc.). Bayer’s pharma business participates in virtually all of these segments. How does a Company like Bayer approach the development of a portfolio in a space as large and as diverse as this one? How does Bayer approach the support of the production infrastructure with unique demands and significant differences from its historical requirements? Moderator:

Shinichiro Fuse, PhD

  • Managing Partner, MPM Capital

Speaker: Wolfram Carius, PhD

  • EVP, Pharmaceuticals, Head of Cell & Gene Therapy, Bayer AG

CGT will bring treatment to cure, delivery of therapies 

Be a Leader repair, regenerate, cure

Technology and Science for CGT – building a portfolio vs single asset decision criteria development of IP market access patients access acceleration of new products

Bayer strategy: build platform for use by four domains  

Gener augmentation

Autologeneic therapy, analytics

Gene editing

Oncology Cell therapy tumor treatment: What kind of cells – the jury is out

Of 23 product launch at Bayer no prediction is possible some high some lows 

  • Q&A 1:00 PM – 1:15 PM  

12:55 PM – 1:35 PM

Lunch

  1:40 PM – 2:05 PM

GCT Delivery | Perfecting the Technology

Gene delivery uses physical, chemical, or viral means to introduce genetic material into cells. As more genetically modified therapies move closer to the market, challenges involving safety, efficacy, and manufacturing have emerged. Optimizing lipidic and polymer nanoparticles and exosomal delivery is a short-term priority. This panel will examine how the short-term and long-term challenges are being tackled particularly for non-viral delivery modalities. Moderator: Natalie Artzi, PhD

  • Assistant Professor, BWH

Speakers: Geoff McDonough, MD

  • CEO, Generation Bio

Sonya Montgomery

  • CMO, Evox Therapeutics

Laura Sepp-Lorenzino, PhD

  • Chief Scientific Officer, Executive Vice President, Intellia Therapeutics

Doug Williams, PhD

  • CEO, Codiak BioSciences
  • Q&A 2:10 PM – 2:25 PM  

2:05 PM – 2:10 PM

Invention Discovery Grant Announcement

  2:10 PM – 2:20 PM FIRST LOOK

Enhancing vesicles for therapeutic delivery of bioproducts

Xandra Breakefield, PhD

  • Geneticist, MGH, MGH
  • Professor, Neurology, HMS
  • Q&A 2:20 PM – 2:35 PM  

2:20 PM – 2:30 PM FIRST LOOK

Versatile polymer-based nanocarriers for targeted therapy and immunomodulation

Natalie Artzi, PhD

  • Assistant Professor, BWH
  • Q&A 2:30 PM – 2:45 PM  

2:55 PM – 3:20 PM HOT TOPICS

Gene Editing | Achieving Therapeutic Mainstream

Gene editing was recognized by the Nobel Committee as “one of gene technology’s sharpest tools, having a revolutionary impact on life sciences.” Introduced in 2011, gene editing is used to modify DNA. It has applications across almost all categories of disease and is also being used in agriculture and public health.

Today’s panel is made up of pioneers who represent foundational aspects of gene editing.  They will discuss the movement of the technology into the therapeutic mainstream.

  • Successes in gene editing – lessons learned from late-stage assets (sickle cell, ophthalmology)
  • When to use what editing tool – pros and cons of traditional gene-editing v. base editing.  Is prime editing the future? Specific use cases for epigenetic editing.
  • When we reach widespread clinical use – role of off-target editing – is the risk real?  How will we mitigate? How practical is patient-specific off-target evaluation?

Moderator: J. Keith Joung, MD, PhD

  • Robert B. Colvin, M.D. Endowed Chair in Pathology & Pathologist, MGH
  • Professor of Pathology, HMS

Speakers: John Evans

  • CEO, Beam Therapeutics

Lisa Michaels

  • EVP & CMO, Editas Medicine
  • Q&A 3:25 PM – 3:50 PM  

3:25 PM – 3:50 PM HOT TOPICS

Common Blood Disorders | Gene Therapy

There are several dozen companies working to develop gene or cell therapies for Sickle Cell Disease, Beta Thalassemia, and  Fanconi Anemia. In some cases, there are enzyme replacement therapies that are deemed effective and safe. In other cases, the disease is only managed at best. This panel will address a number of questions that are particular to this class of genetic diseases:

  • What are the pros and cons of various strategies for treatment? There are AAV-based editing, non-viral delivery even oligonucleotide recruitment of endogenous editing/repair mechanisms. Which approaches are most appropriate for which disease?
  • How can companies increase the speed of recruitment for clinical trials when other treatments are available? What is the best approach to educate patients on a novel therapeutic?
  • How do we best address ethnic and socio-economic diversity to be more representative of the target patient population?
  • How long do we have to follow up with the patients from the scientific, patient’s community, and payer points of view? What are the current FDA and EMA guidelines for long-term follow-up?
  • Where are we with regards to surrogate endpoints and their application to clinically meaningful endpoints?
  • What are the emerging ethical dilemmas in pediatric gene therapy research? Are there challenges with informed consent and pediatric assent for trial participation?
  • Are there differences in reimbursement policies for these different blood disorders? Clearly durability of response is a big factor. Are there other considerations?

Moderator: David Scadden, MD

  • Director, Center for Regenerative Medicine; Co-Director, Harvard Stem Cell Institute, Director, Hematologic Malignancies & Experimental Hematology, MGH
  • Jordan Professor of Medicine, HMS

Speakers: Samarth Kukarni, PhDNick Leschly

  • Chief Bluebird, Bluebird Bio

Mike McCune, MD, PhD

  • Head, HIV Frontiers, Global Health Innovative Technology Solutions, Bill & Melinda Gates Foundation
  • Q&A 3:55 PM – 4:15 PM  

3:50 PM – 4:00 PM FIRST LOOK

Gene Editing

J. Keith Joung, MD, PhD

  • Robert B. Colvin, M.D. Endowed Chair in Pathology & Pathologist, MGH
  • Professor of Pathology, HMS
  • Q&A 4:00 PM – 4:20 PM  

4:20 PM – 4:45 PM HOT TOPICS

Gene Expression | Modulating with Oligonucleotide-Based Therapies

Oligonucleotide drugs have recently come into their own with approvals from companies such as Biogen, Alnylam, Novartis and others. This panel will address several questions:

How important is the delivery challenge for oligonucleotides? Are technological advancements emerging that will improve the delivery of oligonucleotides to the CNS or skeletal muscle after systemic administration?

  • Will oligonucleotides improve as a class that will make them even more effective?   Are further advancements in backbone chemistry anticipated, for example.
  • Will oligonucleotide based therapies blaze trails for follow-on gene therapy products?
  • Are small molecules a threat to oligonucleotide-based therapies?
  • Beyond exon skipping and knock-down mechanisms, what other roles will oligonucleotide-based therapies take mechanistically — can genes be activating oligonucleotides?  Is there a place for multiple mechanism oligonucleotide medicines?
  • Are there any advantages of RNAi-based oligonucleotides over ASOs, and if so for what use?

Moderator: Jeannie Lee, MD, PhD

  • Molecular Biologist, MGH
  • Professor of Genetics, HMS

Speakers: Bob Brown, PhD

  • CSO, EVP of R&D, Dicerna

Brett Monia, PhD

  • CEO, Ionis

Alfred Sandrock, MD, PhD

  • EVP, R&D and CMO, Biogen
  • Q&A 4:50 PM – 5:05 PM  

4:45 PM – 4:55 PM FIRST LOOK

RNA therapy for brain cancer

Pierpaolo Peruzzi, MD, PhD

  • Nuerosurgery, BWH
  • Assistant Professor of Neurosurgery, HMS
  • Q&A 4:55 PM – 5:15 PM  

Friday, May 21, 2021

8:30 AM – 8:55 AM

Venture Investing | Shaping GCT Translation

What is occurring in the GCT venture capital segment? Which elements are seeing the most activity? Which areas have cooled? How is the investment market segmented between gene therapy, cell therapy and gene editing? What makes a hot GCT company? How long will the market stay frothy? Some review of demographics — # of investments, sizes, etc. Why is the market hot and how long do we expect it to stay that way? Rank the top 5 geographic markets for GCT company creation and investing? Are there academic centers that have been especially adept at accelerating GCT outcomes? Do the business models for the rapid development of coronavirus vaccine have any lessons for how GCT technology can be brought to market more quickly? Moderator: Meredith Fisher, PhD

  • Partner, Mass General Brigham Innovation Fund

Speakers: David Berry, MD, PhD

  • CEO, Valo Health
  • General Partner, Flagship Pioneering

Robert Nelsen

  • Managing Director, Co-founder, ARCH Venture Partners

Kush Parmar, MD, PhD

  • Managing Partner, 5AM Ventures
  • Q&A 9:00 AM – 9:15 AM  

9:00 AM – 9:25 AM

Regenerative Medicine | Stem Cells

The promise of stem cells has been a highlight in the realm of regenerative medicine. Unfortunately, that promise remains largely in the future. Recent breakthroughs have accelerated these potential interventions in particular for treating neurological disease. Among the topics the panel will consider are:

  • Stem cell sourcing
  • Therapeutic indication growth
  • Genetic and other modification in cell production
  • Cell production to final product optimization and challenges
  • How to optimize the final product

Moderator: Ole Isacson, MD, PhD

  • Director, Neuroregeneration Research Institute, McLean
  • Professor, Neurology and Neuroscience, HMS

Speakers: Kapil Bharti, PhD

  • Senior Investigator, Ocular and Stem Cell Translational Research Section, NIH

Joe Burns, PhD

  • VP, Head of Biology, Decibel Therapeutics

Erin Kimbrel, PhD

  • Executive Director, Regenerative Medicine, Astellas

Nabiha Saklayen, PhD

  • CEO and Co-Founder, Cellino
  • Q&A 9:30 AM – 9:45 AM  

9:25 AM – 9:35 AM FIRST LOOK

Stem Cells

Bob Carter, MD, PhD

  • Chairman, Department of Neurosurgery, MGH
  • William and Elizabeth Sweet, Professor of Neurosurgery, HMS
  • Q&A 9:35 AM – 9:55 AM  

9:35 AM – 10:00 AM

Capital Formation ’21-30 | Investing Modes Driving GCT Technology and Timing

The dynamics of venture/PE investing and IPOs are fast evolving. What are the drivers – will the number of investors grow will the size of early rounds continue to grow? How is this reflected in GCT target areas, company design, and biotech overall? Do patients benefit from these trends? Is crossover investing a distinct class or a little of both? Why did it emerge and what are the characteristics of the players?  Will SPACs play a role in the growth of the gene and cell therapy industry. What is the role of corporate investment arms eg NVS, Bayer, GV, etc. – has a category killer emerged?  Are we nearing the limit of what the GCT market can absorb or will investment capital continue to grow unabated? Moderator: Roger Kitterman

  • VP, Venture, Mass General Brigham

Speakers: Ellen Hukkelhoven, PhD

  • Managing Director, Perceptive Advisors

Peter Kolchinsky, PhD

  • Founder and Managing Partner, RA Capital Management

Deep Nishar

  • Senior Managing Partner, SoftBank Investment Advisors

Oleg Nodelman

  • Founder & Managing Partner, EcoR1 Capital
  • Q&A 10:05 AM – 10:20 AM  

10:00 AM – 10:10 AM FIRST LOOK

New scientific and clinical developments for autologous stem cell therapy for Parkinson’s disease patients

Penelope Hallett, PhD

  • NRL, McLean
  • Assistant Professor Psychiatry, HMS
  • Q&A 10:10 AM – 10:30 AM  

10:10 AM – 10:35 AM HOT TOPICS

Neurodegenerative Clinical Outcomes | Achieving GCT Success

Can stem cell-based platforms become successful treatments for neurodegenerative diseases?

  •  What are the commonalities driving GCT success in neurodegenerative disease and non-neurologic disease, what are the key differences?
  • Overcoming treatment administration challenges
  • GCT impact on degenerative stage of disease
  • How difficult will it be to titrate the size of the cell therapy effect in different neurological disorders and for different patients?
  • Demonstrating clinical value to patients and payers
  • Revised clinical trial models to address issues and concerns specific to GCT

Moderator: Bob Carter, MD, PhD

  • Chairman, Department of Neurosurgery, MGH
  • William and Elizabeth Sweet, Professor of Neurosurgery, HMS

Speakers: Erwan Bezard, PhD

  • INSERM Research Director, Institute of Neurodegenerative Diseases

Nikola Kojic, PhD

  • CEO and Co-Founder, Oryon Cell Therapies

Geoff MacKay

  • President & CEO, AVROBIO

Viviane Tabar, MD

  • Founding Investigator, BlueRock Therapeutics
  • Chair of Neurosurgery, Memorial Sloan Kettering
  • Q&A 10:40 AM – 10:55 AM  

10:35 AM – 11:35 AM

Disruptive Dozen: 12 Technologies that Will Reinvent GCT

Nearly one hundred senior Mass General Brigham Harvard faculty contributed to the creation of this group of twelve GCT technologies that they believe will breakthrough in the next two years. The Disruptive Dozen identifies and ranks the GCT technologies that will be available on at least an experimental basis to have the chance of significantly improving health care. 11:35 AM – 11:45 AM

Concluding Remarks

Friday, May 21, 2021

Computer connection to the iCloud of WordPress.com FROZE completely at 10:30AM EST and no file update was possible. COVERAGE OF MAY 21, 2021 IS RECORDED BELOW FOLLOWING THE AGENDA BY COPY AN DPASTE OF ALL THE TWEETS I PRODUCED ON MAY 21, 2021 8:30 AM – 8:55 AM

Venture Investing | Shaping GCT Translation

What is occurring in the GCT venture capital segment? Which elements are seeing the most activity? Which areas have cooled? How is the investment market segmented between gene therapy, cell therapy and gene editing? What makes a hot GCT company? How long will the market stay frothy? Some review of demographics — # of investments, sizes, etc. Why is the market hot and how long do we expect it to stay that way? Rank the top 5 geographic markets for GCT company creation and investing? Are there academic centers that have been especially adept at accelerating GCT outcomes? Do the business models for the rapid development of coronavirus vaccine have any lessons for how GCT technology can be brought to market more quickly? Moderator: Meredith Fisher, PhD

  • Partner, Mass General Brigham Innovation Fund

Speakers: David Berry, MD, PhD

  • CEO, Valo Health
  • General Partner, Flagship Pioneering

Robert Nelsen

  • Managing Director, Co-founder, ARCH Venture Partners

Kush Parmar, MD, PhD

  • Managing Partner, 5AM Ventures
  • Q&A 9:00 AM – 9:15 AM  

9:00 AM – 9:25 AM

Regenerative Medicine | Stem Cells

The promise of stem cells has been a highlight in the realm of regenerative medicine. Unfortunately, that promise remains largely in the future. Recent breakthroughs have accelerated these potential interventions in particular for treating neurological disease. Among the topics the panel will consider are:

  • Stem cell sourcing
  • Therapeutic indication growth
  • Genetic and other modification in cell production
  • Cell production to final product optimization and challenges
  • How to optimize the final product

Moderator: Ole Isacson, MD, PhD

  • Director, Neuroregeneration Research Institute, McLean
  • Professor, Neurology and Neuroscience, HMS

Speakers: Kapil Bharti, PhD

  • Senior Investigator, Ocular and Stem Cell Translational Research Section, NIH

Joe Burns, PhD

  • VP, Head of Biology, Decibel Therapeutics

Erin Kimbrel, PhD

  • Executive Director, Regenerative Medicine, Astellas

Nabiha Saklayen, PhD

  • CEO and Co-Founder, Cellino
  • Q&A 9:30 AM – 9:45 AM  

9:25 AM – 9:35 AM FIRST LOOK

Stem Cells

Bob Carter, MD, PhD

  • Chairman, Department of Neurosurgery, MGH
  • William and Elizabeth Sweet, Professor of Neurosurgery, HMS
  • Q&A 9:35 AM – 9:55 AM  

9:35 AM – 10:00 AM

Capital Formation ’21-30 | Investing Modes Driving GCT Technology and Timing

The dynamics of venture/PE investing and IPOs are fast evolving. What are the drivers – will the number of investors grow will the size of early rounds continue to grow? How is this reflected in GCT target areas, company design, and biotech overall? Do patients benefit from these trends? Is crossover investing a distinct class or a little of both? Why did it emerge and what are the characteristics of the players?  Will SPACs play a role in the growth of the gene and cell therapy industry. What is the role of corporate investment arms eg NVS, Bayer, GV, etc. – has a category killer emerged?  Are we nearing the limit of what the GCT market can absorb or will investment capital continue to grow unabated? Moderator: Roger Kitterman

  • VP, Venture, Mass General Brigham

Speakers: Ellen Hukkelhoven, PhD

  • Managing Director, Perceptive Advisors

Peter Kolchinsky, PhD

  • Founder and Managing Partner, RA Capital Management

Deep Nishar

  • Senior Managing Partner, SoftBank Investment Advisors

Oleg Nodelman

  • Founder & Managing Partner, EcoR1 Capital
  • Q&A 10:05 AM – 10:20 AM  

10:00 AM – 10:10 AM FIRST LOOK

New scientific and clinical developments for autologous stem cell therapy for Parkinson’s disease patients

Penelope Hallett, PhD

  • NRL, McLean
  • Assistant Professor Psychiatry, HMS
  • Q&A 10:10 AM – 10:30 AM  

10:10 AM – 10:35 AM HOT TOPICS

Neurodegenerative Clinical Outcomes | Achieving GCT Success

Can stem cell-based platforms become successful treatments for neurodegenerative diseases?

  •  What are the commonalities driving GCT success in neurodegenerative disease and non-neurologic disease, what are the key differences?
  • Overcoming treatment administration challenges
  • GCT impact on degenerative stage of disease
  • How difficult will it be to titrate the size of the cell therapy effect in different neurological disorders and for different patients?
  • Demonstrating clinical value to patients and payers
  • Revised clinical trial models to address issues and concerns specific to GCT

Moderator: Bob Carter, MD, PhD

  • Chairman, Department of Neurosurgery, MGH
  • William and Elizabeth Sweet, Professor of Neurosurgery, HMS

Speakers: Erwan Bezard, PhD

  • INSERM Research Director, Institute of Neurodegenerative Diseases

Nikola Kojic, PhD

  • CEO and Co-Founder, Oryon Cell Therapies

Geoff MacKay

  • President & CEO, AVROBIO

Viviane Tabar, MD

  • Founding Investigator, BlueRock Therapeutics
  • Chair of Neurosurgery, Memorial Sloan Kettering
  • Q&A 10:40 AM – 10:55 AM  

10:35 AM – 11:35 AM

Disruptive Dozen: 12 Technologies that Will Reinvent GCT

Nearly one hundred senior Mass General Brigham Harvard faculty contributed to the creation of this group of twelve GCT technologies that they believe will breakthrough in the next two years. The Disruptive Dozen identifies and ranks the GCT technologies that will be available on at least an experimental basis to have the chance of significantly improving health care. 11:35 AM – 11:45 AM

Concluding Remarks

The co-chairs convene to reflect on the insights shared over the three days. They will discuss what to expect at the in-person GCT focused May 2-4, 2022 World Medical Innovation Forum.

 

The co-chairs convene to reflect on the insights shared over the three days. They will discuss what to expect at the in-person GCT focused May 2-4, 2022 World Medical Innovation Forum.Christine Seidman, MD

Hypertrophic and Dilated Cardiomyopaies ‘

10% receive heart transplant 12 years survival 

Mutation puterb function

TTN: contribute 20% of dilated cardiomyopaty

Silence gene 

pleuripotential cells deliver therapies 

  • Q&A 11:00 AM – 11:20 AM  

11:00 AM – 11:10 AM FIRST LOOK

Unlocking the secret lives of proteins in health and disease

Anna Greka, MD, PhD

  • Medicine, BWH
  • Associate Professor, Medicine, HMS

Cyprus Island, kidney disease by mutation causing MUC1 accumulation and death BRD4780 molecule that will clear the misfolding proteins from the kidney organoids: pleuripotent stem cells small molecule developed for applications in the other cell types in brain, eye, gene mutation build mechnism for therapy clinical models transition from Academia to biotech 

Q&A

  • 11:10 AM – 11:30 AM  

11:10 AM – 11:35 AM

Rare and Ultra Rare Diseases | GCT Breaks Through

One of the most innovative segments in all of healthcare is the development of GCT driven therapies for rare and ultra-rare diseases. Driven by a series of insights and tools and funded in part by disease focused foundations, philanthropists and abundant venture funding disease after disease is yielding to new GCT technology. These often become platforms to address more prevalent diseases. The goal of making these breakthroughs routine and affordable is challenged by a range of issues including clinical trial design and pricing.

  • What is driving the interest in rare diseases?
  • What are the biggest barriers to making breakthroughs ‘routine and affordable?’
  • What is the role of retrospective and prospective natural history studies in rare disease?  When does the expected value of retrospective disease history studies justify the cost?
  • Related to the first question, what is the FDA expecting as far as controls in clinical trials for rare diseases?  How does this impact the collection of natural history data?

Moderator: Susan Slaugenhaupt, PhD

  • Scientific Director and Elizabeth G. Riley and Daniel E. Smith Jr., Endowed Chair, Mass General Research Institute
  • Professor, Neurology, HMS

Speakers: Leah Bloom, PhD

  • SVP, External Innovation and Strategic Alliances, Novartis Gene Therapies

Ultra rare (less than 100) vs rare difficulty to recruit patients and to follow up after treatment Bobby Gaspar, MD, PhD

  • CEO, Orchard Therapeutics

Study of rare condition have transfer to other larger diseases – delivery of therapeutics genes, like immune disorders 

Patient testimonials just to hear what a treatment can make Emil Kakkis, MD, PhD

  • CEO, Ultragenyx

Do 100 patient study then have information on natural history to develop a clinical trial Stuart Peltz, PhD

  • CEO, PTC Therapeutics

Rare disease, challenge for FDA approval and after market commercialization follow ups

Justification of cost for Rare disease – demonstration of Change is IP in value patients advocacy is helpful

  • Q&A 11:40 AM – 11:55 AM  

11:40 AM – 12:00 PM FIRESIDE

Partnering Across the GCT Spectrum

  Moderator: Erin Harris

  • Chief Editor, Cell & Gene

Perspective & professional tenure

Partnership in manufacturing what are the recommendations?

Hospital systems: Partnership Challenges  Speaker: Marc Casper

  • CEO, ThermoFisher

25 years in Diagnostics last 20 years at ThermoFisher 

products used in the Lab for CAR-T research and manufacture 

CGT Innovations: FDA will have a high level of approval each year

How move from research to clinical trials to manufacturing Quicker process

Best practices in Partnerships: the root cause if acceleration to market service providers to deliver highest standards

Building capacity by acquisition to avoid the waiting time

Accelerate new products been manufactured 

Collaborations with Academic Medical center i.e., UCSF in CGT joint funding to accelerate CGT to clinics’

Customers are extremely knowledgable, scale the capital investment made investment

150MIL a year to improve the Workflow 

  • Q&A 12:05 PM – 12:20 PM  

12:05 PM – 12:30 PM

CEO Panel | Anticipating Disruption | Planning for Widespread GCT

The power of GCT to cure disease has the prospect of profoundly improving the lives of patients who respond. Planning for a disruption of this magnitude is complex and challenging as it will change care across the spectrum. Leading chief executives shares perspectives on how the industry will change and how this change should be anticipated. Moderator: Meg Tirrell

  • Senior Health and Science Reporter, CNBC

CGT becoming staple therapy what are the disruptors emerging Speakers: Lisa Dechamps

  • SVP & Chief Business Officer, Novartis Gene Therapies

Reimagine medicine with collaboration at MGH, MDM condition in children 

The Science is there, sustainable processes and systems impact is transformational

Value based pricing, risk sharing Payers and Pharma for one time therapy with life span effect

Collaboration with FDAKieran Murphy

  • CEO, GE Healthcare

Diagnosis of disease to be used in CGT

2021 investment in CAR-T platform 

Investment in several CGT frontier

Investment in AI, ML in system design new technologies 

GE: Scale and Global distributions, sponsor companies in software 

Waste in Industry – Healthcare % of GDP, work with MGH to smooth the workflow faster entry into hospital and out of Hospital

Telemedicine during is Pandemic: Radiologist needs to read remotely 

Supply chain disruptions slow down all ecosystem 

Production of ventilators by collaboration with GM – ingenuity 

Scan patients outside of hospital a scanner in a Box Christian Rommel, PhD

  • Head, Pharmaceuticals Research & Development, Bayer AG

CGT – 2016 and in 2020 new leadership and capability 

Disease Biology and therapeutics

Regenerative Medicine: CGT vs repair building pipeline in ophthalmology and cardiovascular 

During Pandemic: Deliver Medicines like Moderna, Pfizer – collaborations between competitors with Government Bayer entered into Vaccines in 5 days, all processes had to change access innovations developed over decades for medical solutions 

  • Q&A 12:35 PM – 12:50 PM  

12:35 PM – 12:55 PM FIRESIDE

Building a GCT Portfolio

GCT represents a large and growing market for novel therapeutics that has several segments. These include Cardiovascular Disease, Cancer, Neurological Diseases, Infectious Disease, Ophthalmology, Benign Blood Disorders, and many others; Manufacturing and Supply Chain including CDMO’s and CMO’s; Stem Cells and Regenerative Medicine; Tools and Platforms (viral vectors, nano delivery, gene editing, etc.). Bayer’s pharma business participates in virtually all of these segments. How does a Company like Bayer approach the development of a portfolio in a space as large and as diverse as this one? How does Bayer approach the support of the production infrastructure with unique demands and significant differences from its historical requirements? Moderator:

Shinichiro Fuse, PhD

  • Managing Partner, MPM Capital

Speaker: Wolfram Carius, PhD

  • EVP, Pharmaceuticals, Head of Cell & Gene Therapy, Bayer AG

CGT will bring treatment to cure, delivery of therapies 

Be a Leader repair, regenerate, cure

Technology and Science for CGT – building a portfolio vs single asset decision criteria development of IP market access patients access acceleration of new products

Bayer strategy: build platform for use by four domains  

Gener augmentation

Autologeneic therapy, analytics

Gene editing

Oncology Cell therapy tumor treatment: What kind of cells – the jury is out

Of 23 product launch at Bayer no prediction is possible some high some lows 

  • Q&A 1:00 PM – 1:15 PM  

12:55 PM – 1:35 PM

Lunch

  1:40 PM – 2:05 PM

GCT Delivery | Perfecting the Technology

Gene delivery uses physical, chemical, or viral means to introduce genetic material into cells. As more genetically modified therapies move closer to the market, challenges involving safety, efficacy, and manufacturing have emerged. Optimizing lipidic and polymer nanoparticles and exosomal delivery is a short-term priority. This panel will examine how the short-term and long-term challenges are being tackled particularly for non-viral delivery modalities. Moderator: Natalie Artzi, PhD

  • Assistant Professor, BWH

Speakers: Geoff McDonough, MD

  • CEO, Generation Bio

Sonya Montgomery

  • CMO, Evox Therapeutics

Laura Sepp-Lorenzino, PhD

  • Chief Scientific Officer, Executive Vice President, Intellia Therapeutics

Doug Williams, PhD

  • CEO, Codiak BioSciences
  • Q&A 2:10 PM – 2:25 PM  

2:05 PM – 2:10 PM

Invention Discovery Grant Announcement

  2:10 PM – 2:20 PM FIRST LOOK

Enhancing vesicles for therapeutic delivery of bioproducts

Xandra Breakefield, PhD

  • Geneticist, MGH, MGH
  • Professor, Neurology, HMS
  • Q&A 2:20 PM – 2:35 PM  

2:20 PM – 2:30 PM FIRST LOOK

Versatile polymer-based nanocarriers for targeted therapy and immunomodulation

Natalie Artzi, PhD

  • Assistant Professor, BWH
  • Q&A 2:30 PM – 2:45 PM  

2:55 PM – 3:20 PM HOT TOPICS

Gene Editing | Achieving Therapeutic Mainstream

Gene editing was recognized by the Nobel Committee as “one of gene technology’s sharpest tools, having a revolutionary impact on life sciences.” Introduced in 2011, gene editing is used to modify DNA. It has applications across almost all categories of disease and is also being used in agriculture and public health.

Today’s panel is made up of pioneers who represent foundational aspects of gene editing.  They will discuss the movement of the technology into the therapeutic mainstream.

  • Successes in gene editing – lessons learned from late-stage assets (sickle cell, ophthalmology)
  • When to use what editing tool – pros and cons of traditional gene-editing v. base editing.  Is prime editing the future? Specific use cases for epigenetic editing.
  • When we reach widespread clinical use – role of off-target editing – is the risk real?  How will we mitigate? How practical is patient-specific off-target evaluation?

Moderator: J. Keith Joung, MD, PhD

  • Robert B. Colvin, M.D. Endowed Chair in Pathology & Pathologist, MGH
  • Professor of Pathology, HMS

Speakers: John Evans

  • CEO, Beam Therapeutics

Lisa Michaels

  • EVP & CMO, Editas Medicine
  • Q&A 3:25 PM – 3:50 PM  

3:25 PM – 3:50 PM HOT TOPICS

Common Blood Disorders | Gene Therapy

There are several dozen companies working to develop gene or cell therapies for Sickle Cell Disease, Beta Thalassemia, and  Fanconi Anemia. In some cases, there are enzyme replacement therapies that are deemed effective and safe. In other cases, the disease is only managed at best. This panel will address a number of questions that are particular to this class of genetic diseases:

  • What are the pros and cons of various strategies for treatment? There are AAV-based editing, non-viral delivery even oligonucleotide recruitment of endogenous editing/repair mechanisms. Which approaches are most appropriate for which disease?
  • How can companies increase the speed of recruitment for clinical trials when other treatments are available? What is the best approach to educate patients on a novel therapeutic?
  • How do we best address ethnic and socio-economic diversity to be more representative of the target patient population?
  • How long do we have to follow up with the patients from the scientific, patient’s community, and payer points of view? What are the current FDA and EMA guidelines for long-term follow-up?
  • Where are we with regards to surrogate endpoints and their application to clinically meaningful endpoints?
  • What are the emerging ethical dilemmas in pediatric gene therapy research? Are there challenges with informed consent and pediatric assent for trial participation?
  • Are there differences in reimbursement policies for these different blood disorders? Clearly durability of response is a big factor. Are there other considerations?

Moderator: David Scadden, MD

  • Director, Center for Regenerative Medicine; Co-Director, Harvard Stem Cell Institute, Director, Hematologic Malignancies & Experimental Hematology, MGH
  • Jordan Professor of Medicine, HMS

Speakers: Samarth Kukarni, PhDNick Leschly

  • Chief Bluebird, Bluebird Bio

Mike McCune, MD, PhD

  • Head, HIV Frontiers, Global Health Innovative Technology Solutions, Bill & Melinda Gates Foundation
  • Q&A 3:55 PM – 4:15 PM  

3:50 PM – 4:00 PM FIRST LOOK

Gene Editing

J. Keith Joung, MD, PhD

  • Robert B. Colvin, M.D. Endowed Chair in Pathology & Pathologist, MGH
  • Professor of Pathology, HMS
  • Q&A 4:00 PM – 4:20 PM  

4:20 PM – 4:45 PM HOT TOPICS

Gene Expression | Modulating with Oligonucleotide-Based Therapies

Oligonucleotide drugs have recently come into their own with approvals from companies such as Biogen, Alnylam, Novartis and others. This panel will address several questions:

How important is the delivery challenge for oligonucleotides? Are technological advancements emerging that will improve the delivery of oligonucleotides to the CNS or skeletal muscle after systemic administration?

  • Will oligonucleotides improve as a class that will make them even more effective?   Are further advancements in backbone chemistry anticipated, for example.
  • Will oligonucleotide based therapies blaze trails for follow-on gene therapy products?
  • Are small molecules a threat to oligonucleotide-based therapies?
  • Beyond exon skipping and knock-down mechanisms, what other roles will oligonucleotide-based therapies take mechanistically — can genes be activating oligonucleotides?  Is there a place for multiple mechanism oligonucleotide medicines?
  • Are there any advantages of RNAi-based oligonucleotides over ASOs, and if so for what use?

Moderator: Jeannie Lee, MD, PhD

  • Molecular Biologist, MGH
  • Professor of Genetics, HMS

Speakers: Bob Brown, PhD

  • CSO, EVP of R&D, Dicerna

Brett Monia, PhD

  • CEO, Ionis

Alfred Sandrock, MD, PhD

  • EVP, R&D and CMO, Biogen
  • Q&A 4:50 PM – 5:05 PM  

4:45 PM – 4:55 PM FIRST LOOK

RNA therapy for brain cancer

Pierpaolo Peruzzi, MD, PhD

  • Nuerosurgery, BWH
  • Assistant Professor of Neurosurgery, HMS
  • Q&A 4:55 PM – 5:15 PM  

Friday, May 21, 2021

Computer connection to the iCloud of WordPress.com FROZE completely at 10:30AM EST and no file update was possible. COVERAGE OF MAY 21, 2021 IS RECORDED BELOW FOLLOWING THE AGENDA BY COPY AN DPASTE OF ALL THE TWEETS I PRODUCED ON MAY 21, 2021

8:30 AM – 8:55 AM

Venture Investing | Shaping GCT Translation

What is occurring in the GCT venture capital segment? Which elements are seeing the most activity? Which areas have cooled? How is the investment market segmented between gene therapy, cell therapy and gene editing? What makes a hot GCT company? How long will the market stay frothy? Some review of demographics — # of investments, sizes, etc. Why is the market hot and how long do we expect it to stay that way? Rank the top 5 geographic markets for GCT company creation and investing? Are there academic centers that have been especially adept at accelerating GCT outcomes? Do the business models for the rapid development of coronavirus vaccine have any lessons for how GCT technology can be brought to market more quickly? Moderator:   Meredith Fisher, PhD

  • Partner, Mass General Brigham Innovation Fund

Strategies, success what changes are needed in the drug discovery process   Speakers:  

Bring disruptive frontier as a platform with reliable delivery CGT double knock out disease cure all change efficiency and scope human centric vs mice centered right scale of data converted into therapeutics acceleratetion 

Innovation in drugs 60% fails in trial because of Toxicology system of the future deal with big diseases

Moderna is an example in unlocking what is inside us Microbiome and beyond discover new drugs epigenetics  

  • Robert Nelsen
    • Managing Director, Co-founder, ARCH Venture Partners

Manufacturing change is not a new clinical trial FDA need to be presented with new rethinking for big innovations Drug pricing cheaper requires systematization How to systematically scaling up systematize the discovery and the production regulatory innovations

Responsibility mismatch should be and what is “are”

Long term diseases Stack holders and modalities risk benefir for populations 

  • Q&A 9:00 AM – 9:15 AM  

9:00 AM – 9:25 AM

Regenerative Medicine | Stem Cells

The promise of stem cells has been a highlight in the realm of regenerative medicine. Unfortunately, that promise remains largely in the future. Recent breakthroughs have accelerated these potential interventions in particular for treating neurological disease. Among the topics the panel will consider are:

  • Stem cell sourcing
  • Therapeutic indication growth
  • Genetic and other modification in cell production
  • Cell production to final product optimization and challenges
  • How to optimize the final product
  • Moderator:
    • Ole Isacson, MD, PhD
      • Director, Neuroregeneration Research Institute, McLean
      • Professor, Neurology and Neuroscience, MGH, HMS

Opportunities in the next generation of the tactical level Welcome the oprimism and energy level of all Translational medicine funding stem cells enormous opportunities 

  • Speakers:
  • Kapil Bharti, PhD
    • Senior Investigator, Ocular and Stem Cell Translational Research Section, NIH
    • first drug required to establish the process for that innovations design of animal studies not done before
    • Off-th-shelf one time treatment becoming cure 
    •  Intact tissue in a dish is fragile to maintain metabolism
    Joe Burns, PhD
    • VP, Head of Biology, Decibel Therapeutics
    • Ear inside the scall compartments and receptors responsible for hearing highly differentiated tall ask to identify cell for anticipated differentiation
    • multiple cell types and tissue to follow
    Erin Kimbrel, PhD
    • Executive Director, Regenerative Medicine, Astellas
    • In the ocular space immunogenecity
    • regulatory communication
    • use gene editing for immunogenecity Cas1 and Cas2 autologous cells
    • gene editing and programming big opportunities 
    Nabiha Saklayen, PhD
    • CEO and Co-Founder, Cellino
    • scale production of autologous cells foundry using semiconductor process in building cassettes
    • solution for autologous cells
  • Q&A 9:30 AM – 9:45 AM  

9:25 AM – 9:35 AM FIRST LOOK

Stem Cells

Bob Carter, MD, PhD

  • Chairman, Department of Neurosurgery, MGH
  • William and Elizabeth Sweet, Professor of Neurosurgery, HMS
  • Cell therapy for Parkinson to replace dopamine producing cells lost ability to produce dopamin
  • skin cell to become autologous cells reprograms to become cells producing dopamine
  • transplantation fibroblast cells metabolic driven process lower mutation burden 
  • Quercetin inhibition elimination undifferentiated cells graft survival oxygenation increased 
  • Q&A 9:35 AM – 9:55 AM  

9:35 AM – 10:00 AM

Capital Formation ’21-30 | Investing Modes Driving GCT Technology and Timing

The dynamics of venture/PE investing and IPOs are fast evolving. What are the drivers – will the number of investors grow will the size of early rounds continue to grow? How is this reflected in GCT target areas, company design, and biotech overall? Do patients benefit from these trends? Is crossover investing a distinct class or a little of both? Why did it emerge and what are the characteristics of the players?  Will SPACs play a role in the growth of the gene and cell therapy industry. What is the role of corporate investment arms eg NVS, Bayer, GV, etc. – has a category killer emerged?  Are we nearing the limit of what the GCT market can absorb or will investment capital continue to grow unabated? Moderator: Roger Kitterman

  • VP, Venture, Mass General Brigham
  • Saturation reached or more investment is coming in CGT 

Speakers: Ellen Hukkelhoven, PhD

  • Managing Director, Perceptive Advisors
  • Cardiac area transduct cells
  • matching tools
  • 10% success of phase 1 in drug development next phase matters more 

Peter Kolchinsky, PhD

  • Founder and Managing Partner, RA Capital Management
  • Future proof for new comers disruptors 
  • Ex Vivo gene therapy to improve funding products what tool kit belongs to 
  • company insulation from next instability vs comapny stabilizing themselves along few years
  • Company interested in SPAC 
  • cross over investment vs SPAC
  • Multi Omics in cancer early screening metastatic diseas will be wiped out 

Deep Nishar

  • Senior Managing Partner, SoftBank Investment Advisors
  • Young field vs CGT started in the 80s 
  • high payloads is a challenge
  • cost effective fast delivery to large populations
  • Mission oriented by the team and management  
  • Multi Omics disease modality 

Oleg Nodelman

  • Founder & Managing Partner, EcoR1 Capital
  • Invest in company next round of investment will be IPO
  • Help company raise money cross over investment vs SPAC
  • Innovating ideas from academia in need for funding 
  • Q&A 10:05 AM – 10:20 AM  

10:00 AM – 10:10 AM FIRST LOOK

New scientific and clinical developments for autologous stem cell therapy for Parkinson’s disease patients

Penelope Hallett, PhD

  • NRL, McLean
  • Assistant Professor Psychiatry, HMS
  • Pharmacologic agent in existing cause another disorders locomo-movement related 
  • efficacy Autologous cell therapy transplantation approach program T cells into dopamine generating neurons greater than Allogeneic cell transplantation 
  • Q&A 10:10 AM – 10:30 AM  

10:10 AM – 10:35 AM HOT TOPICS

Neurodegenerative Clinical Outcomes | Achieving GCT Success

Can stem cell-based platforms become successful treatments for neurodegenerative diseases?

  •  What are the commonalities driving GCT success in neurodegenerative disease and non-neurologic disease, what are the key differences?
  • Overcoming treatment administration challenges
  • GCT impact on degenerative stage of disease
  • How difficult will it be to titrate the size of the cell therapy effect in different neurological disorders and for different patients?
  • Demonstrating clinical value to patients and payers
  • Revised clinical trial models to address issues and concerns specific to GCT

Moderator: Bob Carter, MD, PhD

  • Chairman, Department of Neurosurgery, MGH
  • William and Elizabeth Sweet, Professor of Neurosurgery, HMS
  • Neurogeneration REVERSAL or slowing down 

Speakers: Erwan Bezard, PhD

  • INSERM Research Director, Institute of Neurodegenerative Diseases
  • Cautious on reversal 
  • Early intervantion versus late

Nikola Kojic, PhD

  • CEO and Co-Founder, Oryon Cell Therapies
  • Autologus cell therapy placed focal replacing missing synapses reestablishment of neural circuitary

Geoff MacKay

  • President & CEO, AVROBIO
  • Prevent condition to be manifested in the first place 
  • clinical effect durable single infusion preventions of symptoms to manifest 
  • Cerebral edema – stabilization
  • Gene therapy know which is the abnormal gene grafting the corrected one 
  • More than biomarker as end point functional benefit not yet established  

Viviane Tabar, MD

  • Founding Investigator, BlueRock Therapeutics
  • Chair of Neurosurgery, Memorial Sloan Kettering
  • Current market does not have delivery mechanism that a drug-delivery is the solution Trials would fail on DELIVERY
  • Immune suppressed patients during one year to avoid graft rejection Autologous approach of Parkinson patient genetically mutated reprogramed as dopamine generating neuron – unknowns are present
  • Circuitry restoration
  • Microenvironment disease ameliorate symptoms – education of patients on the treatment 
  • Q&A 10:40 AM – 10:55 AM  

10:35 AM – 11:35 AM

Disruptive Dozen: 12 Technologies that Will Reinvent GCT

Nearly one hundred senior Mass General Brigham Harvard faculty contributed to the creation of this group of twelve GCT technologies that they believe will breakthrough in the next two years. The Disruptive Dozen identifies and ranks the GCT technologies that will be available on at least an experimental basis to have the chance of significantly improving health care. 11:35 AM – 11:45 AM

Concluding Remarks

The co-chairs convene to reflect on the insights shared over the three days. They will discuss what to expect at the in-person GCT focused May 2-4, 2022 World Medical Innovation Forum.

ALL THE TWEETS PRODUCED ON MAY 21, 2021 INCLUDE THE FOLLOWING:

Aviva Lev-Ari

@AVIVA1950

  • @AVIVA1950_PIcs

4h

#WMIF2021

@MGBInnovation

Erwan Bezard, PhD INSERM Research Director, Institute of Neurodegenerative Diseases Cautious on reversal

@pharma_BI

@AVIVA1950

Aviva Lev-Ari

@AVIVA1950

  • @AVIVA1950_PIcs

4h

#WMIF2021

@MGBInnovation

Nikola Kojic, PhD CEO and Co-Founder, Oryon Cell Therapies Autologus cell therapy placed focal replacing missing synapses reestablishment of neural circutary

@pharma_BI

@AVIVA1950

@AVIVA1950_PIcs

Aviva Lev-Ari

@AVIVA1950

4h

#WMIF2021

@MGBInnovation

Bob Carter, MD, PhD Chairman, Department of Neurosurgery, MGH William and Elizabeth Sweet, Professor of Neurosurgery, HMS Neurogeneration REVERSAL or slowing down? 

@pharma_BI

@AVIVA1950

@AVIVA1950_PIcs

Aviva Lev-Ari

@AVIVA1950

4h

#WMIF2021

@MGBInnovation

Penelope Hallett, PhD NRL, McLean Assistant Professor Psychiatry, HMS efficacy Autologous cell therapy transplantation approach program T cells into dopamine genetating cells greater than Allogeneic cell transplantation 

@pharma_BI

@AVIVA1950

@AVIVA1950_PIcs

Aviva Lev-Ari

@AVIVA1950

4h

#WMIF2021

@MGBInnovation

Penelope Hallett, PhD NRL, McLean Assistant Professor Psychiatry, HMS Pharmacologic agent in existing cause another disorders locomo-movement related 

@pharma_BI

@AVIVA1950

@AVIVA1950_PIcs

Aviva Lev-Ari

@AVIVA1950

@AVIVA1950_PIcs

4h

#WMIF2021

@MGBInnovation

Roger Kitterman VP, Venture, Mass General Brigham Saturation reached or more investment is coming in CGT Multi OMICS and academia originated innovations are the most attractive areas

@pharma_BI

@AVIVA1950

1

3

@AVIVA1950_PIcs

Aviva Lev-Ari

@AVIVA1950

@AVIVA1950_PIcs

4h

#WMIF2021

@MGBInnovation

Roger Kitterman VP, Venture, Mass General Brigham Saturation reached or more investment is coming in CGT 

@pharma_BI

@AVIVA1950

1

@AVIVA1950_PIcs

Aviva Lev-Ari

@AVIVA1950

4h

#WMIF2021

@MGBInnovation

Oleg Nodelman Founder & Managing Partner, EcoR1 Capital Invest in company next round of investment will be IPO 20% discount

@pharma_BI

@AVIVA1950

@AVIVA1950_PIcs

Aviva Lev-Ari

@AVIVA1950

@AVIVA1950_PIcs

4h

#WMIF2021

@MGBInnovation

Peter Kolchinsky, PhD Founder and Managing Partner, RA Capital Management Future proof for new comers disruptors  Ex Vivo gene therapy to improve funding products what tool kit belongs to 

@pharma_BI

@AVIVA1950

@AVIVA1950_PIcs

Aviva Lev-Ari

@AVIVA1950

4h

#WMIF2021

@MGBInnovation

Deep Nishar Senior Managing Partner, SoftBank Investment Advisors Young field vs CGT started in the 80s  high payloads is a challenge 

@pharma_BI

@AVIVA1950

@AVIVA1950_PIcs

Aviva Lev-Ari

@AVIVA1950

5h

#WMIF2021

@MGBInnovation

Bob Carter, MD, PhD MGH, HMS cells producing dopamine transplantation fibroblast cells metabolic driven process lower mutation burden  Quercetin inhibition elimination undifferentiated cells graft survival oxygenation increased 

@pharma_BI

@AVIVA1950

@AVIVA1950_PIcs

Aviva Lev-Ari

@AVIVA1950

5h

#WMIF2021

@MGBInnovation

Chairman, Department of Neurosurgery, MGH, Professor of Neurosurgery, HMS Cell therapy for Parkinson to replace dopamine producing cells lost ability to produce dopamine skin cell to become autologous cells reprogramed  

@pharma_BI

@AVIVA1950

#WMIF2021

@MGBInnovation

Kapil Bharti, PhD Senior Investigator, Ocular and Stem Cell Translational Research Section, NIH Off-th-shelf one time treatment becoming cure  Intact tissue in a dish is fragile to maintain metabolism to become like semiconductors

@pharma_BI

@AVIVA1950

@AVIVA1950_PIcs

Aviva Lev-Ari

@AVIVA1950

@AVIVA1950_PIcs

5h

#WMIF2021

@MGBInnovation

Ole Isacson, MD, PhD Director, Neuroregeneration Research Institute, McLean Professor, Neurology and Neuroscience, MGH, HMS Opportunities in the next generation of the tactical level Welcome the oprimism and energy level of all

@pharma_BI

@AVIVA1950

@AVIVA1950_PIcs

Aviva Lev-Ari

@AVIVA1950

5h

#WMIF2021

@MGBInnovation

Erin Kimbrel, PhD Executive Director, Regenerative Medicine, Astellas In the ocular space immunogenecity regulatory communication use gene editing for immunogenecity Cas1 and Cas2 autologous cells

@pharma_BI

@AVIVA1950

@AVIVA1950_PIcs

Aviva Lev-Ari

@AVIVA1950

5h

#WMIF2021

@MGBInnovation

Nabiha Saklayen, PhD CEO and Co-Founder, Cellino scale production of autologous cells foundry using semiconductor process in building cassettes by optic physicists

@pharma_BI

@AVIVA1950

@AVIVA1950_PIcs

Aviva Lev-Ari

@AVIVA1950

5h

#WMIF2021

@MGBInnovation

Joe Burns, PhD VP, Head of Biology, Decibel Therapeutics Ear inside the scall compartments and receptors responsible for hearing highly differentiated tall ask to identify cell for anticipated differentiation control by genomics

@pharma_BI

@AVIVA1950

Aviva Lev-Ari

@AVIVA1950

5h

#WMIF2021

@MGBInnovation

Kapil Bharti, PhD Senior Investigator, Ocular and Stem Cell Translational Research Section, NIH first drug required to establish the process for that innovations design of animal studies not done before 

@pharma_BI

@AVIVA1950

@AVIVA1950_PIcs

Aviva Lev-Ari

@AVIVA1950

5h

#WMIF2021

@MGBInnovation

Meredith Fisher, PhD Partner, Mass General Brigham Innovation Fund Strategies, success what changes are needed in the drug discovery process@pharma_BI

@AVIVA1950

@AVIVA1950_PIcs

Aviva Lev-Ari

@AVIVA1950

5h

#WMIF2021

@MGBInnovation

Robert Nelsen Managing Director, Co-founder, ARCH Venture Partners Manufacturing change is not a new clinical trial FDA need to be presented with new rethinking for big innovations Drug pricing cheaper requires systematization

@pharma_BI

@AVIVA1950

1

@AVIVA1950_PIcs

Aviva Lev-Ari

@AVIVA1950

5h

#WMIF2021

@MGBInnovation

Kush Parmar, MD, PhD Managing Partner, 5AM Ventures Responsibility mismatch should be and what is “are”

@pharma_BI

@AVIVA1950

@AVIVA1950_PIcs

Aviva Lev-Ari

@AVIVA1950

5h

#WMIF2021

@MGBInnovation

David Berry, MD, PhD CEO, Valo Health GP, Flagship Pioneering Bring disruptive frontier platform reliable delivery CGT double knockout disease cure all change efficiency scope human centric vs mice centered right scale acceleration

@pharma_BI

@AVIVA1950

@AVIVA1950_PIcs

Aviva Lev-Ari

@AVIVA1950

6h

#WMIF2021

@MGBInnovation

Kush Parmar, MD, PhD Managing Partner, 5AM Ventures build it yourself, benefit for patients FIrst Look at MGB shows MEE innovation on inner ear worthy investment  

@pharma_BI

@AVIVA1950

@AVIVA1950_PIcs

Aviva Lev-Ari

@AVIVA1950

6h

#WMIF2021

@MGBInnovation

Robert Nelsen Managing Director, Co-founder, ARCH Venture Partners Frustration with supply chain during the Pandemic, GMC anticipation in advance CGT rapidly prototype rethink and invest proactive investor .edu and Pharma

@pharma_BI

@AVIVA1950

Read Full Post »

Retrospective Study of National Danish Registry Sheds Light on Cardiotoxic Risks of Immune Checkpoint Inhibitors

Reporter: Adina Hazan, PhD

 

Immune checkpoint inhibitors are used to treat over 12 different types of cancers, as a way of encouraging T cells of the immune system to target and kill cancer cells. While this method has proved to be an incredibly important mechanism in fighting deadly cancers, the enhanced immune response has been documented to produce a wide array of side effects, including an increased incidence of cardiovascular events such as arrhythmias and sudden cardiac arrest. Due to the nature of the disease and treatment, most evidence of cardiotoxicity from the treatment comes from small cohorts of patients or individual case studies.

D’Souza and colleagues used four Danish healthcare registries to collect data from over 13,000 patients with malignant melanoma, and over 25,000 patients with lung cancer, starting from 2011 with the introduction of checkpoint inhibitors up until 2017. Each group included patients who received checkpoint inhibitors and those that did not, providing the basis of their retrospective study to determine the risk of developing cardiac events with treatment over a long period of time. The study was published in the European Heart Journal in December 2020.

The authors confirmed the increased risk of cardiac events with the treatment of immune checkpoint inhibitors PD1i and CTLA-4i.

  • The relative rate of cardiovascular deaths were increased in patients with lung cancer treated with PD1i by three-fold, and
  • eight times higher in patients with malignant melanoma treated with CTLA-4i.
  • Moreover, they show increased relative rates of arrhythmias in both diseases treated with PD1i, and malignant melanoma treated with CTLA-4i.
  • This was also true of the timeframe of treatment, where it was previously believed that most cardiac events would develop within the first six months of checkpoint inhibitor use.
  • By using data from patients over years, this study shows that these adverse events develop even after the first six months.

The myocardium, or heart muscle tissue, has previously been reported to be damaged with the use of checkpoint inhibitors, suspected to be due to

  • increasing inflammatory cytokines and enhanced inflammatory pathways. Significantly, previous pharmacovigilance studies have suggested a rate of developing myocarditis at less than 1%, but
  • data from this study shows that the 1 year risk was 1.8%, “suggesting that the risk may be higher than previously estimated”.

Even though Immune checkpoint inhibitors have been shown to be invaluable tools in the treatment of certain cancers, “the findings [in this study] urge increased awareness of cardiac events in patients receiving ICI”.

 

Original Research

The risk of cardiac events in patients receiving immune checkpoint inhibitors: a nationwide Danish study 

European Heart Journal, ehaa884, https://doi.org/10.1093/eurheartj/ehaa884
Published:
 
09 December 2020
 Article history
 

Abstract

graphic
 
 
Aims

The study aimed to estimate the risk of cardiac events in immune checkpoint inhibitor (ICI)-treated patients with lung cancer or malignant melanoma.

Methods and results

The study included consecutive patients with lung cancer or malignant melanoma in 2011–17 nationwide in Denmark. The main composite outcome was cardiac events (arrhythmia, peri- or myocarditis, heart failure) or cardiovascular death. Absolute risks were estimated and the association of ICI and cardiac events was analysed in multivariable Cox models. We included 25 573 patients with lung cancer. Of these, 743 were treated with programmed cell death-1 inhibitor (PD1i) and their 1-year absolute risk of cardiac events was 9.7% [95% confidence interval (CI) 6.8–12.5]. Of the 13 568 patients with malignant melanoma, 145 had PD1i and 212 had cytotoxic T-lymphocyte-associated protein-4 inhibitor (CTLA-4i) treatment. Their 1-year risks were 6.6% (1.8–11.3) and 7.5% (3.7–11.3). The hazard rates of cardiac events were higher in patients with vs. without ICI treatment. Within 6 months from 1st ICI administration, the hazard ratios were 2.14 (95% CI 1.50–3.05) in patients with lung cancer and 4.30 (1.38–13.42) and 4.93 (2.45–9.94) in patients with malignant melanoma with PD1i and CTLA-4i, respectively. After 6 months, HRs were 2.26 (1.27–4.02) for patients with lung cancer and 3.48 (1.91–6.35) for patients with malignant melanoma and CTLA-4i.

Conclusions

Among patients with lung cancer and malignant melanoma, ICI treated had increased rates of cardiac events. The absolute risks were higher in these data compared with previous pharmacovigilance studies (e.g. 1.8% peri-/myocarditis 1-year risk).

 

SOURCES

https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehaa884/6027871

 

Other related articles published in this Open Access Online Scientific Journal include the following:

 

Cardiotoxicity and Cardiomyopathy Related to Drugs Adverse Effects

Curator: Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2013/04/11/cardiotoxicity-and-cardiomyopathy-related-to-drugs-adverse-effects/

 

Cardiology & Oncology Drug Development & Regulation

Authors: Stuart L. Cantor, PhD, and Kadriye Ciftci, PhD

https://pharmaceuticalintelligence.com/2016/01/04/cardiology-oncology-drug-development-regulation/

 

Cardio-oncology and Onco-Cardiology Programs: Treatments for Cancer Patients with a History of Cardiovascular Disease

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/01/08/cardio-oncology-and-onco-cardiology-programs-treatments-for-cancer-patients-with-a-history-of-cardiovascular-disease/

Read Full Post »

Hypertriglyceridemia: Evaluation and Treatment Guideline

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

Severe and very severe hypertriglyceridemia increase the risk for pancreatitis, whereas mild or moderate hypertriglyceridemia may be a risk factor for cardiovascular disease. Individuals found to have any elevation of fasting triglycerides should be evaluated for secondary causes of hyperlipidemia including endocrine conditions and medications. Patients with primary hypertriglyceridemia must be assessed for other cardiovascular risk factors, such as central obesity, hypertension, abnormalities of glucose metabolism, and liver dysfunction. The aim of this study was to develop clinical practice guidelines on hypertriglyceridemia.

The diagnosis of hypertriglyceridemia should be based on fasting levels, that mild and moderate hypertriglyceridemia (triglycerides of 150–999 mg/dl) be diagnosed to aid in the evaluation of cardiovascular risk, and that severe and very severe hypertriglyceridemia (triglycerides of >1000 mg/dl) be considered a risk for pancreatitis. The patients with hypertriglyceridemia must be evaluated for secondary causes of hyperlipidemia and that subjects with primary hypertriglyceridemia be evaluated for family history of dyslipidemia and cardiovascular disease.

The treatment goal in patients with moderate hypertriglyceridemia should be a non-high-density lipoprotein cholesterol level in agreement with National Cholesterol Education Program Adult Treatment Panel guidelines. The initial treatment should be lifestyle therapy; a combination of diet modification, physical activity and drug therapy may also be considered. In patients with severe or very severe hypertriglyceridemia, a fibrate can be used as a first-line agent for reduction of triglycerides in patients at risk for triglyceride-induced pancreatitis.

Three drug classes (fibrates, niacin, n-3 fatty acids) alone or in combination with statins may be considered as treatment options in patients with moderate to severe triglyceride levels. Statins are not be used as monotherapy for severe or very severe hypertriglyceridemia. However, statins may be useful for the treatment of moderate hypertriglyceridemia when indicated to modify cardiovascular risk.

 

References:

 

https://www.medpagetoday.com/clinical-connection/cardio-endo/77242?xid=NL_CardioEndoConnection_2019-01-21

https://www.ncbi.nlm.nih.gov/pubmed/19307519

https://www.ncbi.nlm.nih.gov/pubmed/23009776

https://www.ncbi.nlm.nih.gov/pubmed/6827992

https://www.ncbi.nlm.nih.gov/pubmed/22463676

https://www.ncbi.nlm.nih.gov/pubmed/17635890

 

Read Full Post »

Live 2:30-4:30 PM  Mediterranean Diet and Lifestyle: A Symposium on Diet and Human Health:  October 19, 2018

Reporter: Stephen J. Williams, Ph.D.

 

2:30 Mediterranean Diet, Intangible Heritage and Sustainable Tourism?

Prof. Fabio Parasecoli, PhD.

 

 

Nutrition and Food Department, New York University

We focus on more of the cultural aspects and the relevance of this diet to tourism in Italy where there is a high rate of unemployment.  The diet is interesting from a touristic standpoint as the diet have the perspective of the different ingredients inherent in Italy.  The mediterranean diet food pyramid totally different than US.  How do we explain to consumers these medical concepts; for example in China, Germany they are using different ways to explain the benefits of this diet.

A Cultural Formation

  • a way of life, for tourism there is the way of life people want to adopt (easiest way to do this is go to the Mediterranean and learn the lifestyle)
  • so for example Olive Garden for marketing purposes sent a few chefs for half a day training so the image of learning to cook in the mediterranean diet style can be very powerful communicative tool
  • 2003 UNESCO Convention for Safeguarding the Culturing Heritage: protecting landscapes but then decided to protect other intangible heritage like oral, language, oral traditions like transmitting recipes, social and festive events (how do we cook how do we grow tomatoes, wheat etc)
  • UNESCO: promoted France Gastronomic, Mediterranean Diet, and traditional Mexican Cuisine (Mayan)
  • defined Greece, Italy, Morroco then included Cyprus Crotia and Portugal in the Mediterranean diet
  • has it been used for promotion: no UNESCO did not use this since does not safeguard the culture
  • (gastrodiplomacy); like Korea and kimchie; included in the list of cultural cuisine but can create tourist bubbles as you tourism places like hotels don’t always use; for reasons of economy or safety or accessibility , local food
  • Centrality of Territorio:  food consumed from tourist should come from the area

Sustainable Tourism: a form of tourism where have the intention to get to know the place;

have to think in three ways

  1. environmental
  2. social
  3. cultural

how do we make a circular economy so no waste; for example certain companies using food waste to make other products

Tourism clusters made of many groups; he is working on a way to jump start these networks in Nigeria;

Sustainable Food Supply Chain Tourism can be used as way to engage people and promote the diet

Question: are there regions where people are not adopting the diet because of taste, preferences

Yes there is always a problem with accessibility, affordability, trade issues and regional acceptance. For instance in Australia a big push back against the Mediterranean diet.  Medical professionals need to work with communication experts and media experts in developing ways to communicate the benefits since “no one wants to be preached at” and “as economies get richer people want to be more modern and try new things”

In Nigeria we are working with many different industries like transportation, engineers, the IT industry and chefs to build a scalable model

 

3.00 Italy as a Case Study: Increasing Students’ Level of Awareness of the Historical, Cultural, Political and Culinary Significance of Food

Prof. Lisa Sasson

Nutrition and Food Department, New York University

Started a program at NYU to understand food  from a nutritionist and historical point of view as a cultural heritage in Italy, but when students came back students mentioned it changed their food shopping habits

they described diet as wine, pasta, and olive oil

Artisional Production:  understanding the taste and flavor; she wanted them to learn about the food culture and educate their tastes

Food Memories: how we pass on recipes and food aromas, food tastes.  The students were experienced food in a unique way for the first time, experiencing what cheese, quality oil other foods when fresh tastes like.  Artisional foods may be expensive but need only a little of it because the tastes and flavors are so potent due to the phytochemicals

Within six months students:

  1. increased consumption of weekly wine consumption with meals
  2. increased consuming satisfying meals
  3. increased time consuming meals

In the womb the fetus is actually acquiring sense of taste (amniotic fluid changes with mother diet; can detect flavor chemicals)

Student Perceptions after a study Abroad Program

  • eating foods local and seasonal
  • replacing butter with quality olive oil
  • using herbs
  • very little sugar
  • unsweetened beverages
  • limiting red meats
  • fish a couple of times a week
  • dairy in moderation
  • no processed foods

Eating and Dining for Americans is a Challenge:  The students ate well and satisfying meals but ate alot but did not gain weight

3:30 Italian Migration and Global Diaspora

Dr. Vincenzo Milione, PhD

Director of Demographics Studies, Calandra Institute, City University of New York

for a PDF of this presentation please click heresbarro handout.

Dr. Millione used the U.S. Census Bureau Data to estimate the growth of the Italian diaspora descendants in host countries in the Americas and to determine the mixed global ancestry of Italian descendants.

  • Italian emigration to the US happened in two waves
  1.            Wave 1: early 1900 peaking between 1901 and 1911 (turn of century)
  2.            Wave 2: 1951-1971 (post WWII)

This pattern was similar between North and South America although South American had first Italian immigration; in 1860 we got rid of slavery so many jobs not filled new orleans

Developing a mathematical model of Italian diaspora: the model is centered on the host country population dynamics but descendants are separated into first generation and multi generation

Model dependent on:

  • birth and death rates
  • first generation population growth
  • multi generational population growth
  • emigration from host country over time

He was able to calculate an indices he termed Year of Italianization Change (YIC): the year the growth of the multi generation supercedes the first generation immigrant population 

Country Year of Italianlization Change (YIC)
Brazil 1911
Uruguay 1915
Argentina 1918
USA 1936
Venezuela 1963
Canada 1968
Australia 1988

 

note: as a result there is an increasing loss of language and traditional customs with host country cultural adaptation among the native born descendants

In addition, over the last 20 years Italian-American population growth demonstrates that Italian-American self-identity in the United States has increased.  The census data identified two ancestries of the respondent.  In mixed ancestry Italian-American respondents to the extent they identify Italian first demonstrating the strong Italian-American identity.

The foreign born Italian Americans mirror the immigration pattern of Italian immigration from Italy until 1980 where more Italian Americans self identify as foreign born in other countries and not in Italy

Summary

  • over 5 million Italians have emigrated from Italy from 1980 to present
  • most went to North and South America but many went to other global countries
  • the Italian immigration to the different countries in the Americas varies over the period of mass emigration when the growth of multi generational Italian descendants is greater then first generation Italians (Year of Italianization Change) goes from 1911 in Brazil to 1988 in Australia
  • Immigrants to the USA was not just from Italy but from almost all nations globally over all geographical continents
  • Italina immigrants descendants greatly grew after 1930 with appreciable increase with other ethnicities such that 61% of Italian Americans are mixed ancestry in 2014: to date mixed ancestry represents 98% of Italian Americans
  • younger italian americans more likely to have mixed ancestry with Central and South America, Asian and African ethnicities

over time during immigration eating habits has changed but more research is needed if and how the italian recipes and diet has changed as well

 

4:15 Conclusions

Prof. Antonio Giordano, MD, PhD.

To follow or Tweet on Twitter please use the following handles (@) and hashtags (#):

@ handles


@S_H_R_O 

@SbarroHealth

@Pharma_BI 

@ItalyinPhilly

@WHO_Europe

@nutritionorg

# hashtags


#healthydiet

#MediterraneanDiet

#health

#nutrition

Please see related articles on Live Coverage of Previous Meetings on this Open Access Journal

Real Time Conference Coverage for Scientific and Business Media: Unique Twitter Hashtags and Handles per Conference Presentation/Session

LIVE – Real Time – 16th Annual Cancer Research Symposium, Koch Institute, Friday, June 16, 9AM – 5PM, Kresge Auditorium, MIT

Real Time Coverage and eProceedings of Presentations on 11/16 – 11/17, 2016, The 12th Annual Personalized Medicine Conference, HARVARD MEDICAL SCHOOL, Joseph B. Martin Conference Center, 77 Avenue Louis Pasteur, Boston

Tweets Impression Analytics, Re-Tweets, Tweets and Likes by @AVIVA1950 and @pharma_BI for 2018 BioIT, Boston, 5/15 – 5/17, 2018

BIO 2018! June 4-7, 2018 at Boston Convention & Exhibition Center

LIVE 2018 The 21st Gabay Award to LORENZ STUDER, Memorial Sloan Kettering Cancer Center, contributions in stem cell biology and patient-specific, cell-based therapy

HUBweek 2018, October 8-14, 2018, Greater Boston – “We The Future” – coming together, of breaking down barriers, of convening across disciplinary lines to shape our future

Read Full Post »

Live 12:00 – 1:00 P.M  Mediterranean Diet and Lifestyle: A Symposium on Diet and Human Health : October 19, 2018

Reporter: Stephen J. Williams, Ph.D.

12.00 The Italian Mediterranean Diet as a Model of Identity of a People with a Universal Good to Safeguard Health?

Prof. Antonino De Lorenzo, MD, PhD.

Director of the School of Specialization in Clinical Nutrition, University of Rome “Tor Vergata”

It is important to determine how our bodies interacts with the environment, such as absorption of nutrients.

Studies shown here show decrease in life expectancy of a high sugar diet, but the quality of the diet, not just the type of diet is important, especially the role of natural probiotics and phenolic compounds found in the Mediterranean diet.

The WHO report in 2005 discusses the unsustainability of nutrition deficiencies and suggest a proactive personalized and preventative/predictive approach of diet and health.

Most of the noncommunicable diseases like CV (46%) cancer 21% and 11% respiratory and 4% diabetes could be prevented and or cured with proper dietary approaches

Italy vs. the US diseases: in Italy most disease due to environmental contamination while US diet plays a major role

The issue we are facing in less than 10% of the Italian population (fruit, fibers, oils) are not getting the proper foods, diet and contributing to as we suggest 46% of the disease

The Food Paradox: 1.5 billion are obese; we notice we are eating less products of quality and most quality produce is going to waste;

  •  growing BMI and junk food: our studies are correlating the junk food (pre-prepared) and global BMI
  • modern diet and impact of human health (junk food high in additives, salt) has impact on microflora
  • Western Diet and Addiction: We show a link (using brain scans) showing correlation of junk food, sugar cravings, and other addictive behaviors by affecting the dopamine signaling in the substantia nigra
  • developed a junk food calculator and a Mediterranean diet calculator
  • the intersection of culture, food is embedded in the Mediterranean diet; this is supported by dietary studies of two distinct rural Italian populations (one of these in the US) show decrease in diet
  • Impact of diet: have model in Germany how this diet can increase health and life expectancy
  • from 1950 to present day 2.7 unit increase in the diet index can increase life expectancy by 26%
  • so there is an inverse relationship with our index and breast cancer

Environment and metal contamination and glyphosate: contribution to disease and impact of maintaining the healthy diet

  • huge problem with use of pesticides and increase in celiac disease

12:30 Environment and Health

Dr. Iris Maria Forte, PhD.

National Cancer Institute “Pascale” Foundation | IRCCS · Department of Research, Naples, Italy

Cancer as a disease of the environment.  Weinberg’s hallmarks of Cancer reveal how environment and epigenetics can impact any of these hallmarks.

Epigenetic effects

  • gene gatekeepers (Rb and P53)
  • DNA repair and damage stabilization

Heavy Metals and Dioxins:( alterations of the immune system as well as epigenetic regulations)

Asbestos and Mesothelioma:  they have demonstrated that p53 can be involved in development of mesothelioma as reactivating p53 may be a suitable strategy for therapy

Diet, Tomato and Cancer

  • looked at tomato extract on p53 function in gastric cancer: tomato extract had a growth reduction effect and altered cell cycle regulation and results in apoptosis
  • RBL2 levels are increased in extract amount dependent manner so data shows effect of certain tomato extracts of the southern italian tomato (     )

Antonio Giordano: we tested whole extracts of almost 30 different varieties of tomato.  The tomato variety  with highest activity was near Ravela however black tomatoes have shown high antitumor activity.  We have done a followup studies showing that these varieties, if grow elsewhere lose their antitumor activity after two or three generations of breeding, even though there genetics are similar.  We are also studying the effects of different styles of cooking of these tomatoes and if it reduces antitumor effect

please see post https://news.temple.edu/news/2017-08-28/muse-cancer-fighting-tomatoes-study-italian-food

 

To follow or Tweet on Twitter please use the following handles (@) and hashtags (#):

@ handles


@S_H_R_O 

@SbarroHealth

@Pharma_BI 

@ItalyinPhilly

@WHO_Europe

@nutritionorg

# hashtags


#healthydiet

#MediterraneanDiet

#health

#nutrition

Please see related articles on Live Coverage of Previous Meetings on this Open Access Journal

Real Time Conference Coverage for Scientific and Business Media: Unique Twitter Hashtags and Handles per Conference Presentation/Session

LIVE – Real Time – 16th Annual Cancer Research Symposium, Koch Institute, Friday, June 16, 9AM – 5PM, Kresge Auditorium, MIT

Real Time Coverage and eProceedings of Presentations on 11/16 – 11/17, 2016, The 12th Annual Personalized Medicine Conference, HARVARD MEDICAL SCHOOL, Joseph B. Martin Conference Center, 77 Avenue Louis Pasteur, Boston

Tweets Impression Analytics, Re-Tweets, Tweets and Likes by @AVIVA1950 and @pharma_BI for 2018 BioIT, Boston, 5/15 – 5/17, 2018

BIO 2018! June 4-7, 2018 at Boston Convention & Exhibition Center

LIVE 2018 The 21st Gabay Award to LORENZ STUDER, Memorial Sloan Kettering Cancer Center, contributions in stem cell biology and patient-specific, cell-based therapy

HUBweek 2018, October 8-14, 2018, Greater Boston – “We The Future” – coming together, of breaking down barriers, of convening across disciplinary lines to shape our future

Read Full Post »

 Cholesterol Lowering Novel PCSK9 drugs: Praluent [Sanofi and Regeneron] vs Repatha [Amgen] – which drug cuts CV risks enough to make it cost-effective?

Reporter: Aviva Lev-Ari, PhD, RN

 

UPDATED on 1/15/2019

In the patent fight over PCSK9 inhibitors, the Supreme Court refused to hear Amgen’s appeal of a 2017 court decision allowing Sanofi and Regeneron to continue selling alirocumab (Praluent). Amgen still has a new patent trial starting in Delaware federal court next month, FiercePharma reports.

Amgen’s Repatha hits wall at SCOTUS but presses ahead—new price breaks included

Amgen has been trying since 2015 to protect its PCSK9 cholesterol drug Repatha by keeping Sanofi and Regeneron’s rival Praluent off the market, even going as far as to ask the U.S. Supreme Court to review an ongoing patent fight.

But that attempt fell short this week as SCOTUS refused to hear the company’s appeal of a 2017 court decision allowing Sanofi and Regeneron to continue selling its head-to-head rival.

Amgen isn’t giving up the fight, though. The company is prepping for a new patent trial starting in Delaware federal court next month. And it’s responding to long-standing criticism of the high cost of PCSK9 drugs, which hit the market in 2015 at list prices of about $14,000 a year.

Amgen had already brought the price of the biweekly version of Repatha down to $5,850 per year before discounts and rebates, and late Monday it said it would lower cost of the monthly injectable dose to that same level.

SOURCE

UPDATED on 11/13/2018

ODYSSEY OUTCOMES: Alirocumab Cost-effective at $6000 a Year

Marlene Busko

November 11, 2018

CHICAGO — Treatment with the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor alirocumab (Praluent, Sanofi/Regeneron) is cost-effective at $6319 a year when the willingness-to-pay threshold is the generally accepted $100,000 per quality-adjusted life-year (QALY), new research reports.

Deepak L. Bhatt, MD, MPH, Brigham and Women’s Hospital Heart and Vascular Center, Harvard Medical School, Boston, Massachusetts, presented these cost-effectiveness findings for alirocumab, based on data from the ODYSSEY OUTCOMES trial, here at the American Heart Association (AHA) 2018 Scientific Sessions

As previously reported, results from ODYSSEY OUTCOMES were presented at American College of Cardiology (ACC) 2018 Annual Scientific Session in March and the study was published November 7 in the New England Journal of Medicine.

Strengths of the current cost analysis include that it used actual trial data as opposed to modeling estimates, Bhatt pointed out to theheart.org | Medscape Cardiology.

SOURCE

https://www.medscape.com/viewarticle/904744?nlid=126063_3866&src=WNL_mdplsfeat_181113_mscpedit_card&uac=93761AJ&spon=2&impID=1799507&faf=1

 

Did Amgen’s Repatha cut CV risks enough to make it cost-effective? Analysts say no

Sanofi, Regeneron’s Praluent pulls off PCSK9 coup with 29% cut to death risks in most vulnerable patients
SEE our curations on PCSK9 drugs:

Read Full Post »

SNP-based Study on high BMI exposure confirms CVD and DM Risks – no associations with Stroke, Volume 2 (Volume Two: Latest in Genomics Methodologies for Therapeutics: Gene Editing, NGS and BioInformatics, Simulations and the Genome Ontology), Part 1: Next Generation Sequencing (NGS)

SNP-based Study on high BMI exposure confirms CVD and DM Risks – no associations with Stroke

Reporter: Aviva Lev-Ari, PhD, RN

Genes Affirm: High BMI Carries Weighty Heart, Diabetes Risk – Mendelian randomization study adds to ‘burgeoning evidence’

by Crystal Phend, Senior Associate Editor, MedPage Today, July 05, 2017

 

The “genetically instrumented” measure of high BMI exposure — calculated based on 93 single-nucleotide polymorphisms associated with BMI in prior genome-wide association studies — was associated with the following risks (odds ratios given per standard deviation higher BMI):

  • Hypertension (OR 1.64, 95% CI 1.48-1.83)
  • Coronary heart disease (CHD; OR 1.35, 95% CI 1.09-1.69)
  • Type 2 diabetes (OR 2.53, 95% CI 2.04-3.13)
  • Systolic blood pressure (β 1.65 mm Hg, 95% CI 0.78-2.52 mm Hg)
  • Diastolic blood pressure (β 1.37 mm Hg, 95% CI 0.88-1.85 mm Hg)

However, there were no associations with stroke, Donald Lyall, PhD, of the University of Glasgow, and colleagues reported online in JAMA Cardiology.

The associations independent of age, sex, Townsend deprivation scores, alcohol intake, and smoking history were found in baseline data from 119,859 participants in the population-based U.K. Biobank who had complete medical, sociodemographic, and genetic data.

“The main advantage of an MR approach is that certain types of study bias can be minimized,” the team noted. “Because DNA is stable and randomly inherited, which helps to mitigate errors from reverse causality and confounding, genetic variation can be used as a proxy for lifetime BMI to overcome limitations such as reverse causality and confounding, a process that hampers observational analyses of obesity and its consequences.”

 

Other related articles published in this Open Access Online Scientific Journal include the following:

9 results for Kindle Store : “Aviva Lev-Ari”

Sort by 
Relevance
Featured
Price: Low to High
Price: High to Low
Avg. Customer Review
Publication Date
  • Product Details

    Etiologies of Cardiovascular Diseases: Epigenetics, Genetics and Genomics

    Nov 28, 2015 | Kindle eBook

    by Justin D. Pearlman MD ME PhD MA FACC and Stephen J. Williams PhD
    Subscribers read for free.
    Auto-delivered wirelessly
    Sold by: Amazon Digital Services LLC
  • Product Details

    Perspectives on Nitric Oxide in Disease Mechanisms (Biomed e-Books Book 1)

    Jun 20, 2013 | Kindle eBook

    by Margaret Baker PhD and Tilda Barliya PhD
    Subscribers read for free.
    Auto-delivered wirelessly
    Sold by: Amazon Digital Services LLC
  • Product Details

    Cancer Therapies: Metabolic, Genomics, Interventional, Immunotherapy and Nanotechnology in Therapy Delivery (Series C Book 2)

    May 13, 2017 | Kindle eBook

    by Larry H. Bernstein and Demet Sag
    Subscribers read for free.
    Auto-delivered wirelessly
    Sold by: Amazon Digital Services LLC
  • Product Details

    Metabolic Genomics & Pharmaceutics (BioMedicine – Metabolomics, Immunology, Infectious Diseases Book 1)

    Jul 21, 2015 | Kindle eBook

    by Larry H. Bernstein MD FCAP and Prabodah Kandala PhD
    Subscribers read for free.
    Auto-delivered wirelessly
    Sold by: Amazon Digital Services LLC
  • Product Details

    Milestones in Physiology: Discoveries in Medicine, Genomics and Therapeutics (Series E: Patient-Centered Medicine Book 3)

    Dec 26, 2015 | Kindle eBook

    by Larry H. Bernstein MD FACP and Aviva Lev-Ari PhD RN
    Subscribers read for free.
    Auto-delivered wirelessly
    Sold by: Amazon Digital Services LLC
  • Product Details

    Genomics Orientations for Personalized Medicine (Frontiers in Genomics Research Book 1)

    Nov 22, 2015 | Kindle eBook

    by Sudipta Saha PhD and Ritu Saxena PhD
    Subscribers read for free.
    Auto-delivered wirelessly
    Sold by: Amazon Digital Services LLC
  • Product Details

    Cancer Biology and Genomics for Disease Diagnosis (Series C: e-Books on Cancer & Oncology Book 1)

    Aug 10, 2015 | Kindle eBook

    by Larry H Bernstein MD FCAP and Prabodh Kumar Kandala PhD
    Subscribers read for free.
    Auto-delivered wirelessly
    Sold by: Amazon Digital Services LLC
  • Product Details

    Regenerative and Translational Medicine: The Therapeutic Promise for Cardiovascular Diseases

    Dec 26, 2015 | Kindle eBook

    by Justin D. Pearlman MD ME PhD MA FACC and Stephen J. Williams
    Subscribers read for free.
    Auto-delivered wirelessly
    Sold by: Amazon Digital Services LLC
  • Product Details

    Cardiovascular Original Research: Cases in Methodology Design for Content Co-Curation: The Art of Scientific & Medical Curation

    Nov 29, 2015 | Kindle eBook

    by Larry H. Bernstein MD FCAP and Aviva Lev-Ari PhD RN
    Subscribers read for free.
    Auto-delivered wirelessly

 

Read Full Post »

Coronary Heart Disease Research: Sugar Industry influenced national conversation on heart disease – Adoption of Low Fat Diet vs Low Carbohydrates Diet

Reporter: Aviva Lev-Ari, PhD, RN

Public Health Outcome:

  • Uncontrolled consumption of sugar prevailed 1965 – 2005 – role of sugar in CVD was played down

while

  • Consumption of fat become the diet factor to be control and monitored in the Medical community – role of Fat was the main focus and its management by Statins

and

  • FDA Food Pyramid evolution

USDA Food Pyramid History

In January 1977, after listening to the testimony of Ancel Keys and other doctors and scientists intent on promoting the unsupported Dietary Fat-Heart hypothesis, the Committee published the “Dietary Goals for the United States” recommending that all Americans reduce their fat, saturated fat and cholesterol consumption, and increase their carbohydrate consumption to 55-60% of daily calories.

http://www.healthy-eating-politics.com/usda-food-pyramid.html

Concerns that were raised with the first dietary recommendations 30 y ago have yet to be adequately addressed. The initial Dietary Goals for Americans (1977) proposed increases in carbohydrate intake and decreases in fat, saturated fat, cholesterol, and salt consumption that are carried further in the 2010 Dietary Guidelines Advisory Committee (DGAC) Report. Important aspects of these recommendations remain unproven, yet a dietary shift in this direction has already taken place even as overweight/obesity and diabetes have increased. Although appealing to an evidence-based methodology, the DGAC Report demonstrates several critical weaknesses, including use of an incomplete body of relevant science; inaccurately representing, interpreting, or summarizing the literature; and drawing conclusions and/or making recommendations that do not reflect the limitations or controversies in the science. An objective assessment of evidence in the DGAC Report does not suggest a conclusive proscription against low-carbohydrate diets. The DGAC Report does not provide sufficient evidence to conclude that increases in whole grain and fiber and decreases in dietary saturated fat, salt, and animal protein will lead to positive health outcomes. Lack of supporting evidence limits the value of the proposed recommendations as guidance for consumers or as the basis for public health policy. It is time to reexamine how US dietary guidelines are created and ask whether the current process is still appropriate for our needs.

http://www.nutritionjrnl.com/article/S0899-9007(10)00289-3/abstract

 

Curator: Aviva Lev-Ari, PhD, RN

 

UCSF reveals how sugar industry influenced national conversation on heart disease

 

Special Communication |

Sugar Industry and Coronary Heart Disease Research – A Historical Analysis of Internal Industry Documents

Cristin E. Kearns, DDS, MBA1,2; Laura A. Schmidt, PhD, MSW, MPH1,3,4; Stanton A. Glantz, PhD1,5,6,7,8
JAMA Intern Med. Published online September 12, 2016. doi:10.1001/jamainternmed.2016.5394

Corresponding Author: Stanton A. Glantz, PhD, UCSF Center for Tobacco Control Research and Education, 530 Parnassus Ave, Ste 366, San Francisco, CA 94143-1390 (glantz@medicine.ucsf.edu).

Accepted for Publication: July 2, 2016.

Published Online: September 12, 2016. doi:10.1001/jamainternmed.2016.5394

Author Contributions: Drs Kearns and Glantz had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of data analysis.

Early warning signals of the coronary heart disease (CHD) risk of sugar (sucrose) emerged in the 1950s. We examined Sugar Research Foundation (SRF) internal documents, historical reports, and statements relevant to early debates about the dietary causes of CHD and assembled findings chronologically into a narrative case study. The SRF sponsored its first CHD research project in 1965, a literature review published in the New England Journal of Medicine, which singled out fat and cholesterol as the dietary causes of CHD and downplayed evidence that sucrose consumption was also a risk factor. The SRF set the review’s objective, contributed articles for inclusion, and received drafts. The SRF’s funding and role was not disclosed. Together with other recent analyses of sugar industry documents, our findings suggest the industry sponsored a research program in the 1960s and 1970s that successfully cast doubt about the hazards of sucrose while promoting fat as the dietary culprit in CHD. Policymaking committees should consider giving less weight to food industry–funded studies and include mechanistic and animal studies as well as studies appraising the effect of added sugars on multiple CHD biomarkers and disease development.

These internal documents show that the SRF initiated CHD research in 1965 to protect market share and that its first project, a literature review, was published in NEJM in 1967 without disclosure of the sugar industry’s funding or role. The NEJM review served the sugar industry’s interests by arguing that epidemiologic, animal, and mechanistic studies associating sucrose with CHD were limited, implying they should not be included in an evidentiary assessment of the CHD risks of sucrose. Instead, the review argued that the only evidence modality needed to yield a definitive answer to the question of how to modify the American diet to prevent CHD was RCTs that exclusively used serum cholesterol level as a CHD biomarker. Randomized clinical trials using serum cholesterol level as the CHD biomarker made the high sucrose content of the American diet seem less hazardous than if the entire body of evidence had been considered.

Following the NEJM review, the sugar industry continued to fund research on CHD and other chronic diseases “as a main prop of the industry’s defense.”51 For example, in 1971, it influenced the National Institute of Dental Research’s National Caries Program to shift its emphasis to dental caries interventions other than restricting sucrose.8 The industry commissioned a review, “Sugar in the Diet of Man,” which it credited with, among other industry tactics, favorably influencing the 1976 US Food and Drug Administration evaluation of the safety of sugar.51 These findings, our analysis, and current Sugar Association criticisms of evidence linking sucrose to cardiovascular disease6,7 suggest the industry may have a long history of influencing federal policy.

This historical account of industry efforts demonstrates the importance of having reviews written by people without conflicts of interest and the need for financial disclosure. Scientific reviews shape policy debates, subsequent investigations, and the funding priorities of federal agencies.52 The NEJM has required authors to disclose all conflicts of interest since 1984,53 and conflict of interest disclosure policies have been widely implemented since the sugar industry launched its CHD research program. Whether current conflict of interest policies are adequate to withstand the economic interests of industry remains unclear.54

Many industries sponsor research to influence assessments of the risks and benefits of their products.55– 57The influence of industry sponsorship on nutrition research is receiving increased scrutiny.58 Access to documents not meant for public consumption has provided the public health community unprecedented insight into industry motives, strategies, tactics, and data designed to protect companies from litigation and regulation.59 This insight has been a major factor behind successful global tobacco control policies.60 Our analysis suggests that research using sugar industry documents has the potential to inform the health community about how to counter this industry’s strategies and tactics to control information on the adverse health effects of sucrose.

Study Limitations

The Roger Adams papers and other documents used in this research provide a narrow window into the activities of 1 sugar industry trade association; therefore, it is difficult to validate that the documents gathered are representative of the entirety of SRF internal materials related to Project 226 from the 1950s and 1960s or that the proper weight was given to each data source. There is no direct evidence that the sugar industry wrote or changed the NEJM review manuscript; the evidence that the industry shaped the review’s conclusions is circumstantial. We did not analyze the role of other organizations, nutrition leaders, or food industries that advocated that saturated fat and dietary cholesterol were the main dietary cause of CHD. We could not interview key actors involved in this historical episode because they have died.

This study suggests that the sugar industry sponsored its first CHD research project in 1965 to downplay early warning signals that sucrose consumption was a risk factor in CHD. As of 2016, sugar control policies are being promulgated in international,61 federal,62,63 state, and local venues.64 Yet CHD risk is inconsistently cited as a health consequence of added sugars consumption. Because CHD is the leading cause of death globally, the health community should ensure that CHD risk is evaluated in future risk assessments of added sugars. Policymaking committees should consider giving less weight to food industry–funded studies, and include mechanistic and animal studies as well as studies appraising the effect of added sugars on multiple CHD biomarkers and disease development.65

 

REFERENCES

Council on Foods and Nutrition (American Medical Association).  The regulation of dietary fat: a report of the council. JAMA. 1962;181(5):411-429.
Link to Article

Yudkin  J. Pure, White and Deadly: The Problem of Sugar. London, England: Davis-Poynter Ltd; 1972.

Yudkin  J.  Diet and coronary thrombosis hypothesis and fact. Lancet. 1957;273(6987):155-162.
PubMed   |  Link to Article

Yudkin  J.  Dietary fat and dietary sugar in relation to ischaemic heart-disease and diabetes. Lancet. 1964;2(7349):4-5.
PubMed   |  Link to Article

Technical Group of Committee on Lipoproteins and Atherosclerosis and Committee on Lipoproteins and Atherosclerosis of National Advisory Heart Council.  Evaluation of serum lipoprotein and cholesterol measurements as predictors of clinical complications of atherosclerosis: report of a cooperative study of lipoproteins and atherosclerosisCirculation. 1956;14(4, pt 2):691-742.
PubMed

Albrink  MJ.  Carbohydrate metabolism in cardiovascular disease. Ann Intern Med. 1965;62(6):1330-1333.
PubMed   |  Link to Article

Taubes  G, Couzens  CK. Big sugar’s sweet little lies: how the industry kept scientists from asking, does sugar kill? 2012. http://www.motherjones.com/environment/2012/10/sugar-industry-lies-campaign Accessed October 17, 2014.

Bero  L.  Implications of the tobacco industry documents for public health and policy. Annu Rev Public Health. 2003;24:267-288.
PubMed   |  Link to Article

US Department of Health and Human Services and US Department of Agriculture. 2015-2020 Dietary Guidelines for Americans. 8th ed. Washington, DC: U.S. Government Printing Office; 2016.

US Food and Drug Administration. Changes to the nutrition facts label. 2016.http://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/LabelingNutrition/ucm385663.htm. Accessed June 7, 2016.

Miller  M, Stone  NJ, Ballantyne  C,  et al; American Heart Association Clinical Lipidology, Thrombosis, and Prevention Committee of the Council on Nutrition, Physical Activity, and Metabolism; Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Cardiovascular Nursing; Council on the Kidney in Cardiovascular Disease.  Triglycerides and cardiovascular disease: a scientific statement from the American Heart AssociationCirculation. 2011;123(20):2292-2333.
PubMed   |  Link to Article

Teicholz  N. The Big Fat Surprise: Why Butter, Meat, and Cheese Belong in a Healthy Diet. New York, NY: Simon and Schuster; 2014.

 

Other related articles published in this Open Access Online Scientific Journal include the following:  

 

Metabolomics, Metabonomics and Functional Nutrition: The Next Step in Nutritional Metabolism and Biotherapeutics

Larry H. Bernstein, MD, FCAP  and Aviva Lev-Ari, PhD, RN

Reference Genes in the Human Gut Microbiome: The BGI Catalogue

Aviva Lev-Ari, PhD, RN

Two Mutations, in the PCSK9 Gene: Eliminates a Protein involved in Controlling LDL Cholesterol

Aviva Lev-Ari, PhD, RN

HDL-C: Target of Therapy – Steven E. Nissen, MD, MACC, Cleveland Clinic vs Peter Libby, MD, BWH

Aviva Lev-Ari, PhD, RN

 

The following articles in


Series A: e-Books on Cardiovascular Diseases

Series A Content Consultant: Justin D Pearlman, MD, PhD, FACC

VOLUME THREE

Etiologies of Cardiovascular Diseases:

Epigenetics, Genetics and Genomics

http://www.amazon.com/dp/B018PNHJ84

 

by  

Larry H Bernstein, MD, FCAP, Senior Editor, Author and Curator

and

Aviva Lev-Ari, PhD, RN, Editor and Curator

 

2.2.2: Endothelium, Angiogenesis, and Disordered Coagulation

 

2.2.2.1 What is the Role of Plasma Viscosity in Hemostasis and Vascular Disease Risk? 

Larry H Bernstein, MD, FACP and Aviva Lev-Ari, PhD, RN

 

2.2.2.2 Special Considerations in Blood Lipoproteins, Viscosity, Assessment and Treatment 

Larry H Bernstein, MD, FACP  and Aviva Lev-Ari, PhD, RN

 

2.2.2.3 Biomarkers and risk factors for cardiovascular events, endothelial dysfunction, and thromboembolic complication

Larry H Bernstein, MD, FCAP

 

2.2.2.4 A future for plasma metabolomics in cardiovascular disease assessment  

Larry H Bernstein, MD, FCAP
2.2.2.5 Nitric Oxide Function in Coagulation – Part II

Larry H Bernstein, MD, FACP

 

2.2.2.6 Nitric Oxide, Platelets, Endothelium and Hemostasis (Coagulation Part II)

Larry H Bernstein, MD, FACP

 

2.2.2.7 Peroxisome Proliferator-Activated Receptor (PPAR-gamma) Receptors Activation: PPARγ Transrepression for Angiogenesis in Cardiovascular Disease and PPARγ Transactivation for Treatment of Diabetes 

Aviva Lev-Ari, PhD, RN

Endothelium Inflammatory Biomarkers

 

2.2.2.8 Cardiovascular Risk: C-Reactive Protein BioMarker and Plasma Fibrinogen

Aviva Lev-Ari, PhD, RN

 

2.2.2.9 Cardiovascular Risk Inflammatory Marker: Risk Assessment for Coronary Heart Disease and Ischemic Stroke ­ – Atherosclerosis

Aviva Lev-Ari, PhD, RN

 

2.2.2.10 Importance of high sensitivity C-reactive protein (hs-CRP)

Larry H Bernstein, MD, FCAP

 

See also our Series A: Cardiovascular Diseases

 

flyer-for-series-a-dot16

flyersabcd2-dot16future

metabolomics-seriesdindividualred-page2

Read Full Post »

Genomics and epigenetics link to DNA structure, Volume 2 (Volume Two: Latest in Genomics Methodologies for Therapeutics: Gene Editing, NGS and BioInformatics, Simulations and the Genome Ontology), Part 1: Next Generation Sequencing (NGS)

Genomics and epigenetics link to DNA structure

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

Sequence and Epigenetic Factors Determine Overall DNA Structure

http://www.genengnews.com/gen-news-highlights/sequence-and-epigenetic-factors-determine-overall-dna-structure/81252592/

http://www.genengnews.com/Media/images/GENHighlight/Atomiclevelsimulationsshowingelectrostaticforcesbetweeneachatom1259202113.jpg

Atomic-level simulations show electrostatic forces between each atom. [Alek Aksimentiev, University of Illinois at Urbana-Champaign]

 

The traditionally held hypothesis about the highly ordered organization of DNA describes the interaction of various proteins with DNA sequences to mediate the dynamic structure of the molecule. However, recent evidence has emerged that stretches of homologous DNA sequences can associate preferentially with one another, even in the absence of proteins.

Researchers at the University of Illinois Center for the Physics of Living Cells, Johns Hopkins University, and Ulsan National Institute of Science and Technology (UNIST) in South Korea found that DNA molecules interact directly with one another in ways that are dependent on the sequence of the DNA and epigenetic factors, such as methylation.

The researchers described evidence they found for sequence-dependent attractive interactions between double-stranded DNA molecules that neither involve intermolecular strand exchange nor are mediated by DNA-binding proteins.

“DNA molecules tend to repel each other in water, but in the presence of special types of cations, they can attract each other just like nuclei pulling each other by sharing electrons in between,” explained lead study author Hajin Kim, Ph.D., assistant professor of biophysics at UNIST. “Our study suggests that the attractive force strongly depends on the nucleic acid sequence and also the epigenetic modifications.”

The investigators used atomic-level supercomputer simulations to measure the forces between a pair of double-stranded DNA helices and proposed that the distribution of methyl groups on the DNA was the key to regulating this sequence-dependent attraction. To verify their findings experimentally, the scientists were able to observe a single pair of DNA molecules within nanoscale bubbles.

“Here we combine molecular dynamics simulations with single-molecule fluorescence resonance energy transfer experiments to examine the interactions between duplex DNA in the presence of spermine, a biological polycation,” the authors wrote. “We find that AT-rich DNA duplexes associate more strongly than GC-rich duplexes, regardless of the sequence homology. Methyl groups of thymine act as a steric block, relocating spermine from major grooves to interhelical regions, thereby increasing DNA–DNA attraction.”

The findings from this study were published recently in Nature Communications in an article entitled “Direct Evidence for Sequence-Dependent Attraction Between Double-Stranded DNA Controlled by Methylation.”

After conducting numerous further simulations, the research team concluded that direct DNA–DNA interactions could play a central role in how chromosomes are organized in the cell and which ones are expanded or folded up compactly, ultimately determining functions of different cell types or regulating the cell cycle.

“Biophysics is a fascinating subject that explores the fundamental principles behind a variety of biological processes and life phenomena,” Dr. Kim noted. “Our study requires cross-disciplinary efforts from physicists, biologists, chemists, and engineering scientists and we pursue the diversity of scientific disciplines within the group.”

Dr. Kim concluded by stating that “in our lab, we try to unravel the mysteries within human cells based on the principles of physics and the mechanisms of biology. In the long run, we are seeking for ways to prevent chronic illnesses and diseases associated with aging.”

 

Direct evidence for sequence-dependent attraction between double-stranded DNA controlled by methylation

Jejoong Yoo, Hajin Kim, Aleksei Aksimentiev, and Taekjip Ha
Nature Communications 7 11045 (2016)    DOI:10.1038/ncomms11045BibTex

http://bionano.physics.illinois.edu/sites/default/files/styles/large/public/telepathy_figures_0.png?itok=VUJIHX2_

Although proteins mediate highly ordered DNA organization in vivo, theoretical studies suggest that homologous DNA duplexes can preferentially associate with one another even in the absence of proteins. Here we combine molecular dynamics simulations with single-molecule fluorescence resonance energy transfer experiments to examine the interactions between duplex DNA in the presence of spermine, a biological polycation. We find that AT-rich DNA duplexes associate more strongly than GC-rich duplexes, regardless of the sequence homology. Methyl groups of thymine acts as a steric block, relocating spermine from major grooves to interhelical regions, thereby increasing DNA–DNA attraction. Indeed, methylation of cytosines makes attraction between GC-rich DNA as strong as that between AT-rich DNA. Recent genome-wide chromosome organization studies showed that remote contact frequencies are higher for AT-rich and methylated DNA, suggesting that direct DNA–DNA interactions that we report here may play a role in the chromosome organization and gene regulation.

Formation of a DNA double helix occurs through Watson–Crick pairing mediated by the complementary hydrogen bond patterns of the two DNA strands and base stacking. Interactions between double-stranded (ds)DNA molecules in typical experimental conditions containing mono- and divalent cations are repulsive1, but can turn attractive in the presence of high-valence cations2. Theoretical studies have identified the ion–ion correlation effect as a possible microscopic mechanism of the DNA condensation phenomena3, 4, 5. Theoretical investigations have also suggested that sequence-specific attractive forces might exist between two homologous fragments of dsDNA6, and this ‘homology recognition’ hypothesis was supported by in vitro atomic force microscopy7 and in vivo point mutation assays8. However, the systems used in these measurements were too complex to rule out other possible causes such as Watson–Crick strand exchange between partially melted DNA or protein-mediated association of DNA.

Here we present direct evidence for sequence-dependent attractive interactions between dsDNA molecules that neither involve intermolecular strand exchange nor are mediated by proteins. Further, we find that the sequence-dependent attraction is controlled not by homology—contradictory to the ‘homology recognition’ hypothesis6—but by a methylation pattern. Unlike the previous in vitro study that used monovalent (Na+) or divalent (Mg2+) cations7, we presumed that for the sequence-dependent attractive interactions to operate polyamines would have to be present. Polyamine is a biological polycation present at a millimolar concentration in most eukaryotic cells and essential for cell growth and proliferation9, 10. Polyamines are also known to condense DNA in a concentration-dependent manner2, 11. In this study, we use spermine4+(Sm4+) that contains four positively charged amine groups per molecule.

Sequence dependence of DNA–DNA forces

To characterize the molecular mechanisms of DNA–DNA attraction mediated by polyamines, we performed molecular dynamics (MD) simulations where two effectively infinite parallel dsDNA molecules, 20 base pairs (bp) each in a periodic unit cell, were restrained to maintain a prescribed inter-DNA distance; the DNA molecules were free to rotate about their axes. The two DNA molecules were submerged in 100mM aqueous solution of NaCl that also contained 20 Sm4+molecules; thus, the total charge of Sm4+, 80 e, was equal in magnitude to the total charge of DNA (2 × 2 × 20 e, two unit charges per base pair; Fig. 1a). Repeating such simulations at various inter-DNA distances and applying weighted histogram analysis12 yielded the change in the interaction free energy (ΔG) as a function of the DNA–DNA distance (Fig. 1b,c). In a broad agreement with previous experimental findings13, ΔG had a minimum, ΔGmin, at the inter-DNA distance of 25−30Å for all sequences examined, indeed showing that two duplex DNA molecules can attract each other. The free energy of inter-duplex attraction was at least an order of magnitude smaller than the Watson–Crick interaction free energy of the same length DNA duplex. A minimum of ΔG was not observed in the absence of polyamines, for example, when divalent or monovalent ions were used instead14, 15.

Figure 1: Polyamine-mediated DNA sequence recognition observed in MD simulations and smFRET experiments.
Polyamine-mediated DNA sequence recognition observed in MD simulations and smFRET experiments.

(a) Set-up of MD simulations. A pair of parallel 20-bp dsDNA duplexes is surrounded by aqueous solution (semi-transparent surface) containing 20 Sm4+ molecules (which compensates exactly the charge of DNA) and 100mM NaCl. Under periodic boundary conditions, the DNA molecules are effectively infinite. A harmonic potential (not shown) is applied to maintain the prescribed distance between the dsDNA molecules. (b,c) Interaction free energy of the two DNA helices as a function of the DNA–DNA distance for repeat-sequence DNA fragments (b) and DNA homopolymers (c). (d) Schematic of experimental design. A pair of 120-bp dsDNA labelled with a Cy3/Cy5 FRET pair was encapsulated in a ~200-nm diameter lipid vesicle; the vesicles were immobilized on a quartz slide through biotin–neutravidin binding. Sm4+ molecules added after immobilization penetrated into the porous vesicles. The fluorescence signals were measured using a total internal reflection microscope. (e) Typical fluorescence signals indicative of DNA–DNA binding. Brief jumps in the FRET signal indicate binding events. (f) The fraction of traces exhibiting binding events at different Sm4+ concentrations for AT-rich, GC-rich, AT nonhomologous and CpG-methylated DNA pairs. The sequence of the CpG-methylated DNA specifies the methylation sites (CG sequence, orange), restriction sites (BstUI, triangle) and primer region (underlined). The degree of attractive interaction for the AT nonhomologous and CpG-methylated DNA pairs was similar to that of the AT-rich pair. All measurements were done at [NaCl]=50mM and T=25°C. (g) Design of the hybrid DNA constructs: 40-bp AT-rich and 40-bp GC-rich regions were flanked by 20-bp common primers. The two labelling configurations permit distinguishing parallel from anti-parallel orientation of the DNA. (h) The fraction of traces exhibiting binding events as a function of NaCl concentration at fixed concentration of Sm4+ (1mM). The fraction is significantly higher for parallel orientation of the DNA fragments.

Unexpectedly, we found that DNA sequence has a profound impact on the strength of attractive interaction. The absolute value of ΔG at minimum relative to the value at maximum separation, |ΔGmin|, showed a clearly rank-ordered dependence on the DNA sequence: |ΔGmin| of (A)20>|ΔGmin| of (AT)10>|ΔGmin| of (GC)10>|ΔGmin| of (G)20. Two trends can be noted. First, AT-rich sequences attract each other more strongly than GC-rich sequences16. For example, |ΔGmin| of (AT)10 (1.5kcalmol−1 per turn) is about twice |ΔGmin| of (GC)10 (0.8kcalmol−1 per turn) (Fig. 1b). Second, duplexes having identical AT content but different partitioning of the nucleotides between the strands (that is, (A)20 versus (AT)10 or (G)20 versus (GC)10) exhibit statistically significant differences (~0.3kcalmol−1 per turn) in the value of |ΔGmin|.

To validate the findings of MD simulations, we performed single-molecule fluorescence resonance energy transfer (smFRET)17 experiments of vesicle-encapsulated DNA molecules. Equimolar mixture of donor- and acceptor-labelled 120-bp dsDNA molecules was encapsulated in sub-micron size, porous lipid vesicles18 so that we could observe and quantitate rare binding events between a pair of dsDNA molecules without triggering large-scale DNA condensation2. Our DNA constructs were long enough to ensure dsDNA–dsDNA binding that is stable on the timescale of an smFRET measurement, but shorter than the DNA’s persistence length (~150bp (ref. 19)) to avoid intramolecular condensation20. The vesicles were immobilized on a polymer-passivated surface, and fluorescence signals from individual vesicles containing one donor and one acceptor were selectively analysed (Fig. 1d). Binding of two dsDNA molecules brings their fluorescent labels in close proximity, increasing the FRET efficiency (Fig. 1e).

FRET signals from individual vesicles were diverse. Sporadic binding events were observed in some vesicles, while others exhibited stable binding; traces indicative of frequent conformational transitions were also observed (Supplementary Fig. 1A). Such diverse behaviours could be expected from non-specific interactions of two large biomolecules having structural degrees of freedom. No binding events were observed in the absence of Sm4+ (Supplementary Fig. 1B) or when no DNA molecules were present. To quantitatively assess the propensity of forming a bound state, we chose to use the fraction of single-molecule traces that showed any binding events within the observation time of 2min (Methods). This binding fraction for the pair of AT-rich dsDNAs (AT1, 100% AT in the middle 80-bp section of the 120-bp construct) reached a maximum at ~2mM Sm4+(Fig. 1f), which is consistent with the results of previous experimental studies2, 3. In accordance with the prediction of our MD simulations, GC-rich dsDNAs (GC1, 75% GC in the middle 80bp) showed much lower binding fraction at all Sm4+ concentrations (Fig. 1b,c). Regardless of the DNA sequence, the binding fraction reduced back to zero at high Sm4+ concentrations, likely due to the resolubilization of now positively charged DNA–Sm4+ complexes2, 3, 13.

Because the donor and acceptor fluorophores were attached to the same sequence of DNA, it remained possible that the sequence homology between the donor-labelled DNA and the acceptor-labelled DNA was necessary for their interaction6. To test this possibility, we designed another AT-rich DNA construct AT2 by scrambling the central 80-bp section of AT1 to remove the sequence homology (Supplementary Table 1). The fraction of binding traces for this nonhomologous pair of donor-labelled AT1 and acceptor-labelled AT2 was comparable to that for the homologous AT-rich pair (donor-labelled AT1 and acceptor-labelled AT1) at all Sm4+ concentrations tested (Fig. 1f). Furthermore, this data set rules out the possibility that the higher binding fraction observed experimentally for the AT-rich constructs was caused by inter-duplex Watson–Crick base pairing of the partially melted constructs.

Next, we designed a DNA construct named ATGC, containing, in its middle section, a 40-bp AT-rich segment followed by a 40-bp GC-rich segment (Fig. 1g). By attaching the acceptor to the end of either the AT-rich or GC-rich segments, we could compare the likelihood of observing the parallel binding mode that brings the two AT-rich segments together and the anti-parallel binding mode. Measurements at 1mM Sm4+ and 25 or 50mM NaCl indicated a preference for the parallel binding mode by ~30% (Fig. 1h). Therefore, AT content can modulate DNA–DNA interactions even in a complex sequence context. Note that increasing the concentration of NaCl while keeping the concentration of Sm4+ constant enhances competition between Na+ and Sm4+ counterions, which reduces the concentration of Sm4+ near DNA and hence the frequency of dsDNA–dsDNA binding events (Supplementary Fig. 2).

Methylation determines the strength of DNA–DNA attraction

Analysis of the MD simulations revealed the molecular mechanism of the polyamine-mediated sequence-dependent attraction (Fig. 2). In the case of the AT-rich fragments, the bulky methyl group of thymine base blocks Sm4+ binding to the N7 nitrogen atom of adenine, which is the cation-binding hotspot21, 22. As a result, Sm4+ is not found in the major grooves of the AT-rich duplexes and resides mostly near the DNA backbone (Fig. 2a,d). Such relocated Sm4+ molecules bridge the two DNA duplexes better, accounting for the stronger attraction16, 23, 24, 25. In contrast, significant amount of Sm4+ is adsorbed to the major groove of the GC-rich helices that lacks cation-blocking methyl group (Fig. 2b,e).

Figure 2: Molecular mechanism of polyamine-mediated DNA sequence recognition.
Molecular mechanism of polyamine-mediated DNA sequence recognition.

(ac) Representative configurations of Sm4+ molecules at the DNA–DNA distance of 28Å for the (AT)10–(AT)10 (a), (GC)10–(GC)10 (b) and (GmC)10–(GmC)10 (c) DNA pairs. The backbone and bases of DNA are shown as ribbon and molecular bond, respectively; Sm4+ molecules are shown as molecular bonds. Spheres indicate the location of the N7 atoms and the methyl groups. (df) The average distributions of cations for the three sequence pairs featured in ac. Top: density of Sm4+ nitrogen atoms (d=28Å) averaged over the corresponding MD trajectory and the z axis. White circles (20Å in diameter) indicate the location of the DNA helices. Bottom: the average density of Sm4+ nitrogen (blue), DNA phosphate (black) and sodium (red) atoms projected onto the DNA–DNA distance axis (x axis). The plot was obtained by averaging the corresponding heat map data over y=[−10, 10] Å. See Supplementary Figs 4 and 5 for the cation distributions at d=30, 32, 34 and 36Å.

If indeed the extra methyl group in thymine, which is not found in cytosine, is responsible for stronger DNA–DNA interactions, we can predict that cytosine methylation, which occurs naturally in many eukaryotic organisms and is an essential epigenetic regulation mechanism26, would also increase the strength of DNA–DNA attraction. MD simulations showed that the GC-rich helices containing methylated cytosines (mC) lose the adsorbed Sm4+ (Fig. 2c,f) and that |ΔGmin| of (GC)10 increases on methylation of cytosines to become similar to |ΔGmin| of (AT)10 (Fig. 1b).

To experimentally assess the effect of cytosine methylation, we designed another GC-rich construct GC2 that had the same GC content as GC1 but a higher density of CpG sites (Supplementary Table 1). The CpG sites were then fully methylated using M. SssI methyltransferase (Supplementary Fig. 3; Methods). As predicted from the MD simulations, methylation of the GC-rich constructs increased the binding fraction to the level of the AT-rich constructs (Fig. 1f).

The sequence dependence of |ΔGmin| and its relation to the Sm4+ adsorption patterns can be rationalized by examining the number of Sm4+ molecules shared by the dsDNA molecules (Fig. 3a). An Sm4+ cation adsorbed to the major groove of one dsDNA is separated from the other dsDNA by at least 10Å, contributing much less to the effective DNA–DNA attractive force than a cation positioned between the helices, that is, the ‘bridging’ Sm4+ (ref. 23). An adsorbed Sm4+ also repels other Sm4+ molecules due to like-charge repulsion, lowering the concentration of bridging Sm4+. To demonstrate that the concentration of bridging Sm4+ controls the strength of DNA–DNA attraction, we computed the number of bridging Sm4+ molecules, Nspm (Fig. 3b). Indeed, the number of bridging Sm4+ molecules ranks in the same order as |ΔGmin|: Nspm of (A)20>Nspm of (AT)10Nspm of (GmC)10>Nspm of (GC)10>Nspm of (G)20. Thus, the number density of nucleotides carrying a methyl group (T and mC) is the primary determinant of the strength of attractive interaction between two dsDNA molecules. At the same time, the spatial arrangement of the methyl group carrying nucleotides can affect the interaction strength as well (Fig. 3c). The number of methyl groups and their distribution in the (AT)10 and (GmC)10 duplex DNA are identical, and so are their interaction free energies, |ΔGmin| of (AT)10Gmin| of (GmC)10. For AT-rich DNA sequences, clustering of the methyl groups repels Sm4+ from the major groove more efficiently than when the same number of methyl groups is distributed along the DNA (Fig. 3b). Hence, |ΔGmin| of (A)20>|ΔGmin| of (AT)10. For GC-rich DNA sequences, clustering of the cation-binding sites (N7 nitrogen) attracts more Sm4+ than when such sites are distributed along the DNA (Fig. 3b), hence |ΔGmin| is larger for (GC)10 than for (G)20.

Figure 3: Methylation modulates the interaction free energy of two dsDNA molecules by altering the number of bridging Sm4+.
Methylation modulates the interaction free energy of two dsDNA molecules by altering the number of bridging Sm4+.

(a) Typical spatial arrangement of Sm4+ molecules around a pair of DNA helices. The phosphates groups of DNA and the amine groups of Sm4+ are shown as red and blue spheres, respectively. ‘Bridging’ Sm4+molecules reside between the DNA helices. Orange rectangles illustrate the volume used for counting the number of bridging Sm4+ molecules. (b) The number of bridging amine groups as a function of the inter-DNA distance. The total number of Sm4+ nitrogen atoms was computed by averaging over the corresponding MD trajectory and the 10Å (x axis) by 20Å (y axis) rectangle prism volume (a) centred between the DNA molecules. (c) Schematic representation of the dependence of the interaction free energy of two DNA molecules on their nucleotide sequence. The number and spatial arrangement of nucleotides carrying a methyl group (T or mC) determine the interaction free energy of two dsDNA molecules.

Genome-wide investigations of chromosome conformations using the Hi–C technique revealed that AT-rich loci form tight clusters in human nucleus27, 28. Gene or chromosome inactivation is often accompanied by increased methylation of DNA29 and compaction of facultative heterochromatin regions30. The consistency between those phenomena and our findings suggest the possibility that the polyamine-mediated sequence-dependent DNA–DNA interaction might play a role in chromosome folding and epigenetic regulation of gene expression.

  1. Rau, D. C., Lee, B. & Parsegian, V. A. Measurement of the repulsive force between polyelectrolyte molecules in ionic solution: hydration forces between parallel DNA double helices. Proc. Natl Acad. Sci. USA 81, 26212625 (1984).
  2. Raspaud, E., Olvera de la Cruz, M., Sikorav, J. L. & Livolant, F. Precipitation of DNA by polyamines: a polyelectrolyte behavior. Biophys. J. 74, 381393 (1998).
  3. Besteman, K., Van Eijk, K. & Lemay, S. G. Charge inversion accompanies DNA condensation by multivalent ions. Nat. Phys. 3, 641644 (2007).
  4. Lipfert, J., Doniach, S., Das, R. & Herschlag, D. Understanding nucleic acid-ion interactions.Annu. Rev. Biochem. 83, 813841 (2014).
  5. Grosberg, A. Y., Nguyen, T. T. & Shklovskii, B. I. The physics of charge inversion in chemical and biological systems. Rev. Mod. Phys. 74, 329345 (2002).
  6. Kornyshev, A. A. & Leikin, S. Sequence recognition in the pairing of DNA duplexes. Phys. Rev. Lett. 86, 36663669 (2001).
  7. Danilowicz, C. et al. Single molecule detection of direct, homologous, DNA/DNA pairing.Proc. Natl Acad. Sci. USA 106, 1982419829 (2009).
  8. Gladyshev, E. & Kleckner, N. Direct recognition of homology between double helices of DNA in Neurospora crassa. Nat. Commun. 5, 3509 (2014).
  9. Tabor, C. W. & Tabor, H. Polyamines. Annu. Rev. Biochem. 53, 749790 (1984).
  10. Thomas, T. & Thomas, T. J. Polyamines in cell growth and cell death: molecular mechanisms and therapeutic applications. Cell. Mol. Life Sci. 58, 244258 (2001).

Read Full Post »

Triglycerides: Is it a Risk Factor or a Risk Marker for Atherosclerosis and Cardiovascular Disease ? The Impact of Genetic Mutations on (ANGPTL4) Gene, encoder of (angiopoietin-like 4) Protein, inhibitor of Lipoprotein Lipase

 

Reporters, Curators and Authors: Aviva Lev-Ari, PhD, RN and Larry H. Bernstein, MD, FCAP

Introduction

The role for triglycerides as a risk factor for cardiovascular disease is not new, going back to Donald Frederickson’s classification of hyperlipidemias, at least with respect to Type I and Type IIb. Whether there was a mechanism beyond the observations was yet an open question.  The paper that follows addresses such a question.

 

Large Genetic Studies Support Role For Triglycerides In Cardiovascular Disease

SOURCE

http://cardiobrief.org/2016/03/03/large-genetic-studies-support-role-for-triglycerides-in-cardiovascular-disease/#comments

 

Two  papers published in the New England Journal of Medicine offer new genetic evidence to support the increasingly accepted though still controversial view that triglycerides play an important causal role in cardiovascular disease. If fully validated the new findings could lead to new drugs to prevent and treat cardiovascular disease, though others caution that there is still a long way to go before this could happen.

Both studies describe the impact of genetic mutations on a gene (ANGPTL4) which encodes for a protein (angiopoietin-like 4) that inhibits lipoprotein lipase, an enzyme that plays a key role in breaking down and removing triglycerides from the blood. The large studies found that people with  mutations that inactivate ANGPTL4 have lower levels of triglycerides, higher levels of HDL cholesterol, and decreased risk for cardiovascular disease.

The findings, writes Sander Kersten (Wageningen University, the Netherlands) in an accompanying editorial, “suggest that lowering plasma triglyceride levels is a viable approach to reducing the risk of coronary artery disease.”

The Genetics of Dyslipidemia — When Less Is More

Sander Kersten, Ph.D.   Mar 2, 2016;   http://dx.doi.org:/10.1056/NEJMe1601117

Two groups of investigators now describe in the Journal important genetic evidence showing a causal role of plasma triglycerides in coronary heart disease. Stitziel and colleagues2 tested 54,003 coding-sequence variants covering 13,715 human genes in more than 72,000 patients with coronary artery disease and 120,000 controls. Dewey and colleagues3 sequenced the exons of the gene encoding angiopoietin-like 4 (ANGPTL4) in samples obtained from nearly 43,000 participants in the DiscovEHR human genetics study. The two groups found a significant association between an inactivating mutation (E40K) in ANGPTL4 and both low plasma triglyceride levels and high levels of HDL cholesterol. ANGPTL4 is an inhibitor of lipoprotein lipase, the enzyme that breaks down plasma triglycerides along the capillaries in heart, muscle, and fat.4 Extensive research has shown that ANGPTL4 orchestrates the processing of triglyceride-rich lipoproteins during physiologic conditions such as fasting, exercise, and cold exposure.4 The E40K mutation in ANGPTL4 was previously shown to nearly eliminate the ability of ANGPTL4 to inhibit lipoprotein lipase, a mechanism that may result in part from the destabilization of ANGPTL4.5

The key finding in each study was that carriers of the E40K mutation and other rare mutations in ANGPTL4 had a lower risk of coronary artery disease than did noncarriers, a result that is consistent with the lower triglyceride levels and higher HDL cholesterol levels among mutation carriers. These findings confirm previous data6 and provide convincing genetic evidence that an elevated plasma triglyceride level increases the risk of coronary heart disease. In combination with extensive recent data on other genetic variants that modulate plasma triglyceride levels, the studies suggest that lowering plasma triglyceride levels is a viable approach to reducing the risk of coronary artery disease.

However, as a cautionary note, Talmud and colleagues7 previously found that the presence of the E40K variant was associated with an increased risk of coronary heart disease after adjustment for the altered plasma lipids. Consistent with this hypothesis, the overexpression of Angptl4 in mice was found to protect against atherosclerosis independent of plasma lipids.8

The studies also “implicate targeted inactivation of ANGPTL4 as a potential weapon in the war on heart disease,” though he also points to a previous study that did not support this hypothesis. Sekar Kathiresan (Broad Institute), senior author of one of the NEJM studies, told me that the previous study was small and “basically got the result wrong. Between, the two papers in this NEJM issue, we are looking at 10X more data.”

Recent large genetic studies have resulted in an important change in the field. Many researchers now believe that HDL, which was once thought to play an important protective role in atherosclerosis, is only a marker of disease. In contrast, triglycerides are now thought by many to play an important functional role.

One of the NEJM papers showed that a human monoclonal antibody to ANGPTL4 lowered triglyceride levels in animals. The study was funded by Regeneron and was performed by researchers at Regeneron and Geisinger, as part of an ongoing collaboration using deidentified genetic data from Geisinger patients. In their NEJM paper the researchers reported inflammation and other side effects in the animals treated with the antibody, but they said that no such problem has been observed in humans who have mutations that have the same functional effect as the antibody.

Coding Variation in ANGPTL4, LPL, and SVEP1and the Risk of Coronary Disease Myocardial Infarction Genetics and CARDIoGRAM Exome Consortia Investigators

March 2, 2016     http://dx.doi.org:/10.1056/NEJMoa1507652

Although genomewide association studies have identified more than 56 loci associated with the risk of coronary artery disease,1-3 the disease-associated variants are typically common (minor-allele frequency >5%) and located in noncoding sequences; this has made it difficult to pinpoint causal genes and affected pathways. This lack of a causal mechanism has in part hindered the immediate translation of the findings of genomewide association studies into new therapeutic targets. However, the discovery of rare or low-frequency coding-sequence variants that affect the risk of coronary artery disease has facilitated advances in the prevention and treatment of disease. The most recent example of such advances is the development of a new class of therapeutic agents that is based on the discovery of the gene encoding proprotein convertase subtilisin/kexin type 9 (PCSK9) as a regulator of low-density lipoprotein (LDL) cholesterol4 and the discovery that low-frequency and loss-of-function variants in this gene protect against coronary artery disease.5,6

Recently, low-frequency coding variation across the genome was systematically tabulated with the use of next-generation exome and whole-genome sequencing data from more than 12,000 persons of various ancestries (including a major contribution from the National Heart, Lung, and Blood Institute Exome Sequencing Project). Protein-altering variants (i.e., nonsynonymous, splice-site, and nonsense single-nucleotide substitutions) that were observed at least twice among these 12,000 persons were included in a genotyping array (hereafter referred to as the exome array). In addition, the exome array contains previously described variants from genomewide association studies, a sparse genomewide grid of common markers, markers that are informative with regard to ancestry (i.e., African American, Native American, and European), and some additional content. Additional information on the design of the exome array is provided at http://genome.sph.umich.edu/wiki/Exome_Chip_Design. In this study, we focused on the 220,231 autosomal variants that were present on the array and were expected to alter protein sequence (i.e., missense, nonsense, splice-site, and frameshift variants) and used these to test the contribution of low-frequency coding variation to the risk of coronary artery disease.

Low-Frequency Coding Variants Associated with Coronary Artery Disease

The discovery cohort comprised 120,575 persons (42,335 patients and 78,240 controls) (Table S1 in the Supplementary Appendix). In the discovery cohort, we found significant associations between low-frequency coding variants in theLPA and PCSK9 genes and coronary artery disease (Table 1

TABLE 1

Low-Frequency Coding Variations Previously Associated with Coronary Artery Disease.). Both gene loci also harbor common noncoding variants associated with coronary artery disease that had previously been discovered through genomewide association studies. These variants were also present on the exome array and had significant associations with coronary artery disease in our study (Table 1). In a conditional analysis, the associations between coronary artery disease and the low-frequency coding variants in both LPA and PCSK9 were found to be independent of the associations between coronary artery disease and the more common variants (Table 1). ….

We found a significant association between SVEP1 p.D2702G and blood pressure (Table 3TABLE 3   Association between Low-Frequency Variants and Traditional Risk Factors., and Table S7 in the Supplementary Appendix). The allele associated with an increased risk of coronary artery disease was also associated with higher systolic blood pressure (0.94 mm Hg higher for each copy of the allele among allele carriers, P=3.0×10−7) and higher diastolic blood pressure (0.57 mm Hg higher for each copy of the allele among allele carriers, P=4.4×10−7). We did not find an association between SVEP1 p.D2702G and any plasma lipid trait. In contrast, ANGPTL4 p.E40K was not associated with blood pressure but instead was found to be associated with significantly lower levels of triglycerides (approximately 0.3 standard deviation units lower for each copy of the allele among allele carriers, P=1.6×10−13) (Table 3) and with higher levels of high-density lipoprotein (HDL) cholesterol (approximately 0.3 standard deviation units higher for each copy of the allele among allele carriers, P=8.2×10−11) (Table 3). In a conditional analysis, these effects appeared to be at least partially independent of each other (Table S8 in the Supplementary Appendix). We did not observe any significant association between ANGPTL4 p.E40K and LDL cholesterol level (Table 3). Both SVEP1 p.D2702G and ANGPTL4 p.E40K were nominally associated with type 2 diabetes in a direction concordant with the associated risk of coronary artery disease.

ANGPTL4 Loss-of-Function Mutations, Plasma Lipid Levels, and Coronary Artery Disease

The finding that a missense allele in ANGPTL4 reduced the risk of coronary artery disease, potentially by reducing triglyceride levels, raised the possibility that complete loss-of-function variants in ANGPTL4 may have an even more dramatic effect on triglyceride concentrations and the risk of coronary artery disease. We therefore examined sequence data for the seven protein-coding exons of ANGPTL4 in 6924 patients with early-onset myocardial infarction and 6834 controls free from coronary artery disease (details of the patients and controls are provided in Table S3 in the Supplementary Appendix). We discovered a total of 10 variants that were predicted to lead to loss of gene function (Figure 1A FIGURE 1    

Loss-of-Function Alleles in ANGPTL4 and Plasma Lipid Levels., and Table S9 in the Supplementary Appendix), carried by 28 heterozygous persons; no homozygous or compound heterozygous persons were discovered. Carriers of loss-of-function alleles had significantly lower levels of triglycerides than did noncarriers (a mean of 35% lower among carriers, P=0.003) (Figure 1B, and Table S10 in the Supplementary Appendix), with no significant difference in LDL or HDL cholesterol levels. Moreover, we found a lower risk of coronary artery disease among carriers of loss-of-function alleles (9 carriers among 6924 patients vs. 19 carriers among 6834 controls; odds ratio for disease, 0.47; P=0.04) (Table S11 in the Supplementary Appendix). A similar investigation was performed for the 48 protein-coding exons of SVEP1; however, only 3 loss-of-function allele carriers were discovered (2 carriers among 6924 patients vs. 1 carrier among 6834 controls).

Coding Variation in LPL and the Risk of Coronary Artery Disease

On the basis of the fact that a loss of ANGPTL4 function was associated with reduced risk of coronary artery disease and that ANGPTL4 inhibits lipoprotein lipase (LPL), one would expect a gain of LPL function to also be associated with a lower risk of coronary artery disease, whereas a loss of LPL function would be expected to be associated with a higher risk. In observations consistent with these expectations, we found a low-frequency missense variant in LPL on the exome array that was associated with an increased risk of coronary artery disease (p.D36N; minor-allele frequency, 1.9%; odds ratio for disease, 1.13; P=2.0×10−4) (Table S12 in the Supplementary Appendix); previous studies have shown that this allele (also known as p.D9N) is associated with LPL activity that is 20% lower in allele carriers than in noncarriers.8 We also identified a nonsense mutation in LPL on the exome array that was significantly associated with a reduced risk of coronary artery disease (p.S447*; minor-allele frequency, 9.9%; odds ratio, 0.94; P=2.5×10−7) (Table S12 in the Supplementary Appendix). Contrary to most instances in which the premature introduction of a stop codon leads to loss of gene function, this nonsense mutation, which occurs in the penultimate codon of the gene, paradoxically induces a gain of LPL function.9 …..

Through large-scale exomewide screening, we identified a low-frequency coding variant in ANGPTL4 that was associated with protection against coronary artery disease and a low-frequency coding variant in SVEP1 that was associated with an increased risk of the disease. Moreover, our results highlight LPL as a significant contributor to the risk of coronary artery disease and support the hypothesis that a gain of LPL function or loss of ANGPTL4 inhibition protects against the disease.

ANGPTL4 has previously been found to be involved in cancer pathogenesis and wound healing.10 Previous functional studies also revealed that ANGPTL4 regulates plasma triglyceride concentration by inhibiting LPL.11 The minor allele at p.E40K has previously been associated with lower levels of triglycerides and higher levels of HDL cholesterol.12 We now provide independent confirmation of these lipid effects. In vitro and in vivo experimental evidence suggests that the lysine allele at p.E40K results in destabilization of ANGPTL4 after its secretion from the cell in which it was synthesized. It may be that the p.E40K variant leads to increases in the enzymatic activity of LPL because of this destabilization.13 Previous, smaller studies produced conflicting results regarding p.E40K and the risk of coronary artery disease14,15; we now provide robust support for an association between p.E40K and a reduced risk of coronary artery disease.

An important caveat  to this research is that it is still very early. Most promising therapeutic targets do not work out. James Stein (University of Wisconsin) praised the papers but also offered a word of caution. “This is great science and important research that sheds light on the genetic regulation of TG-rich lipoproteins, serum TG levels, and CVD risk,” he said. “Since it is hard, if not impossible, to disconnect TG-rich lipoproteins from LDL, we should be humble in extrapolating these findings to clinical medicine in an era of low LDL due to statins and PCSK9 inhibitors. I hope this research identifies new targets for drug therapy and better understanding of CVD risk prediction– only time will tell.”

Previous studies with fibrates and other drugs have failed to convincingly show that lowering triglycerides is beneficial. Kathiresan said that what really seems to matter is “how you alter the plasma triglyceride-rich lipoproteins (TRLs).” Some genes that alter TRLs have other metabolic effects. As an example he cited a gene that lowers TRLs but increases the risk for type 2 diabetes. The NEJM papers, by observing the effect of specific mutations, therefore point the way to targets that may be clinically significant.

Conclusions:  The work that has been presented puts a new light on the possible role of triglycerides in the development of congenitally predetermined cardiovascular disease. It does not necessarily establish a general link to mechanism of cardiovascular disease, but it opens up new pathways to our understanding.

SOURCE

http://cardiobrief.org/2016/03/03/large-genetic-studies-support-role-for-triglycerides-in-cardiovascular-disease/#comments

John Contois commented on your update
“Are triglycerides a CHD risk factor? The answer is still maybe. Triglyceride-rich lipoproteins are inextricably linked to LDL metabolism and LDL particle number (and apo B). Still these are important new data and targets for novel therapeutics.”

 

Risk of Dis-lipids Syndromes in Modern Society

 

Risk of Dis-lipids Syndrome in Modern Society

Aurelian Udristioiuᶪ, Manole Cojocaru²
¹Department of Biochemistry, Clinical Laboratory, Emergency County Hospital Targu Jiu & Titu Maiorescu University, Bucharest, Romania,
Department of Physiology, Faculty of Medicine, Titu Maiorescu University, Bucharest, Romania

Abstract
Aim of this work was to emphasis the preclinical evaluation of dis-lipids syndromes types at the patients which were presented to a routine control for checking health status, in the hospital ambulatory.
Material and Method:
Were analyzed 60 patients, registered in Clinical Laboratory, assessing by running on the Hitachi 912 Analyzer, the principal biochemical parameters of lipid metabolism: Cholesterol, Triglycerides and fractions of Cholesterol, HDL and LDL. From the total of 60 patients 35 were females and 25 males.
Results
The persons with an alarm signal of atherosclerotic process were in 28 % and persons with low HDL was in 17%. The cases with atherosclerotic index, report-LDL/HDL>3.5 for men and 2.5 for women were in 14 % , the cases with predictive value with coronary risk, report-CO/HDL>5 were presented in 5 % and the cases with dis-lipid syndrome type 2- 4, with high Cholesterol and Triglycerides, were presented in 30% percent.
Conclusions
Lipids controls, and its fractions, are necessary to be prevented atherosclerotic process in the incipient status of ill.

 

http://video.epccs.eu/video_1466.html

 

 

REFERENCES

http://www.nejm.org/doi/full/10.1056/NEJMe1601117

http://www.nejm.org/doi/full/10.1056/NEJMoa1507652

March 2, 2016 Regeneron Genetics Center Publication in New England Journal of Medicine Links ANGPTL4 Inhibition and Risk of Coronary Artery Disease Demonstrates power of large-scale Precision Medicine initiatives

http://files.shareholder.com/downloads/REGN/1634352863x0x879015/042D3D02-04CB-4DD1-89FE-53927F422025/REGN_News_2016_3_2_General_Releases.pdf

e-Books by Leaders in Pharmaceutical Business Intelligence (LPBI) Group

  • Perspectives on Nitric Oxide in Disease Mechanisms, on Amazon since 6/2/12013

http://www.amazon.com/dp/B00DINFFYC

http://www.amazon.com/dp/B012BB0ZF0

  • Genomics Orientations for Personalized Medicine, on Amazon since 11/23/2015

http://www.amazon.com/dp/B018DHBUO6

  • Milestones in Physiology: Discoveries in Medicine, Genomics and Therapeutics, on Amazon.com since 12/27/2015

http://www.amazon.com/dp/B019VH97LU

  • Cardiovascular, Volume Two: Cardiovascular Original Research: Cases in Methodology Design for Content Co-Curation, on Amazon since 11/30/2015

http://www.amazon.com/dp/B018Q5MCN8

  • Cardiovascular Diseases, Volume Three: Etiologies of Cardiovascular Diseases: Epigenetics, Genetics and Genomics, on Amazon since 11/29/2015

http://www.amazon.com/dp/B018PNHJ84

  • Cardiovascular Diseases, Volume Four: Regenerative and Translational Medicine: The Therapeutics Promise for Cardiovascular Diseases, on Amazon since 12/26/2015

http://www.amazon.com/dp/B019UM909A

Other related articles on this topic published in this Open Access Online Scientific Journal include the following:

Editorial & Publication of Articles in e-Books by  Leaders in Pharmaceutical Business Intelligence:  Contributions of Larry H Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2014/10/16/editorial-publication-of-articles-in-e-books-by-leaders-in-pharmaceutical-business-intelligence-contributions-of-larry-h-bernstein-md-fcap/

Editorial & Publication of Articles in e-Books by Leaders in Pharmaceutical Business Intelligence: Contributions of Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2014/10/16/editorial-publication-of-articles-in-e-books-by-leaders-in-pharmaceutical-business-intelligence-contributions-of-aviva-lev-ari-phd-rn/

TRIGLYCERIDES

http://pharmaceuticalintelligence.com/?s=Triglycerides

HDL

http://pharmaceuticalintelligence.com/?s=HDL

PCSK9

http://pharmaceuticalintelligence.com/?s=PCSK9

STATINS

http://pharmaceuticalintelligence.com/?s=Statins

STATIN

http://pharmaceuticalintelligence.com/?s=STATIN

Read Full Post »

Older Posts »