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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

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Real Time Coverage @BIOConvention #BIO2019: Chat with @FDA Commissioner, & Challenges in Biotech & Gene Therapy June 4 Philadelphia

Reporter: Stephen J. Williams, PhD @StephenJWillia2

 

  • taking patient concerns and voices from anecdotal to data driven system
  • talked about patient accrual hearing patient voice not only in ease of access but reporting toxicities
  • at FDA he wants to remove barriers to trial access and accrual; also talk earlier to co’s on how they should conduct a trial

Digital tech

  • software as medical device
  • regulatory path is mixed like next gen sequencing
  • wearables are concern for FDA (they need to recruit scientists who know this tech

Opioids

  • must address the crisis but in a way that does not harm cancer pain patients
  • smaller pain packs “blister packs” would be good idea

Clinical trial modernization

  • for Alzheimers disease problem is science
  • for diabetes problem is regulatory
  • different diseases calls for different trial design
  • have regulatory problems with rare diseases as can’t form control or placebo group, inhumane. for example ras tumors trials for MEK inhibitors were narrowly focused on certain ras mutants
Realizing the Promise of Gene Therapies for Patients Around the World

103ABC, Level 100

Speakers
Lots of promise, timeline is progressing faster but we need more education on use of the gene therapy
Regulatory issues: Cell and directly delivered gene based therapies have been now approved. Some challenges will be the ultrarare disease trials and how we address manufacturing issues.  Manufacturing is a big issue at CBER and scalability.  If we want to have global impact of these products we need to address the manufacturing issues
 of scalability.
Pfizer – clinical grade and scale is important.
Aventis – he knew manufacturing of biologics however gene therapy manufacturing has its separate issues and is more complicated especially for regulatory purposes for clinical grade as well as scalability.  Strategic decision: focusing on the QC on manufacturing was so important.  Had a major issue in manufacturing had to shut down and redesign the system.
Albert:  Manufacturing is the most important topic even to the investors.  Investors were really conservative especially seeing early problems but when academic centers figured out good efficacy then they investors felt better and market has exploded.  Now you can see investment into preclinical and startups but still want mature companies to focus on manufacturing.  About $10 billion investment in last 4 years.

How Early is Too Early? Valuing and De-Risking Preclinical Opportunities

109AB, Level 100

Speakers
Valuing early-stage opportunities is challenging. Modeling will often provide a false sense of accuracy but relying on comparable transactions is more art than science. With a long lead time to launch, even the most robust estimates can ultimately prove inaccurate. This interactive panel will feature venture capital investors and senior pharma and biotech executives who lead early-stage transactions as they discuss their approaches to valuing opportunities, and offer key learnings from both successful and not-so-successful experiences.
Dr. Schoenbeck, Pfizer:
  • global network of liaisons who are a dedicated team to research potential global startup partners or investments.  Pfizer has a separate team to evaluate academic laboratories.  In Most cases Pfizer does not initiate contact.  It is important to initiate the first discussion with them in order to get noticed.  Could be just a short chat or discussion on what their needs are for their portfolio.

Question: How early is too early?

Luc Marengere, TVM:  His company has early stage focus, on 1st in class molecules.  The sweet spot for their investment is a candidate selected compound, which should be 12-18 months from IND.  They will want to bring to phase II in less than 4 years for $15-17 million.  Their development model is bad for academic labs.  During this process free to talk to other partners.

Dr. Chaudhary, Biogen:  Never too early to initiate a conversation and sometimes that conversation has lasted 3+ years before a decision.  They like build to buy models, will do convertible note deals, candidate compound selection should be entering in GLP/Tox phase (sweet spot)

Merck: have MRL Venture Fund for pre series A funding.  Also reiterated it is never too early to have that initial discussion.  It will not put you in a throw away bin.  They will have suggestions and never like to throw out good ideas.

Michael Hostetler: Set expectations carefully ; data should be validated by a CRO.  If have a platform, they will look at the team first to see if strong then will look at the platform to see how robust it is.

All noted that you should be completely honest at this phase.  Do not overstate your results or data or overhype your compound(s).  Show them everything and don’t have a bias toward compounds you think are the best in your portfolio.  Sometimes the least developed are the ones they are interested in.  Also one firm may reject you however you may fit in others portfolios better so have a broad range of conversations with multiple players.

 

 

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One blood sample can be tested for a comprehensive array of cancer cell biomarkers: R&D at WPI

Curator: Marzan Khan, B.Sc

 

A team of mechanical engineers at Worcester Polytechnic Institute (WPI) have developed a fascinating technology – a liquid biopsy chip that captures and detects metastatic cancer cells, just from a small blood sample of cancer patients(1). This device is a recent development in the scientific field and holds tremendous potential that will allow doctors to spot signs of metastasis for a variety of cancers at an early stage and initiate an appropriate course of treatment(1).

Metastasis occurs when cancer cells break away from their site of origin and spread to other parts of the body via the lymph or the bloodstream, where they give rise to secondary tumors(2). By this time, the cancer is at an advanced stage and it becomes increasingly difficult to fight the disease. The cells that are shed by primary and metastatic cancers are called circulating tumor cells (CTCs) and their numbers lie in the range of 1–77,200/m(3). The basis of the liquid biopsy chip test is to capture these circulating tumor cells in the patient’s blood and identify the cell type through specific interaction with antibodies(4).

The chip is comprised of individual test units or small elements, about 3 millimeters wide(4). Each small element contains a network of carbon nanotube sensors in a well which are functionalized with antibodies(4). These antibodies will bind cell-surface antigens or protein markers unique for each type of cancer cell. Specific interaction between a cell surface protein and its corresponding antibody is a thermodynamic event that causes a change in free energy which is transduced into electricity(3). This electrical signature is picked up by the semi-conducting carbon nanotubes and can be seen as electrical spikes(4). Specific interactions create an increase in electrical signal, whereas non-specific interactions cause a decrease in signal or no change at all(4). Capture efficiency of cancer cells with the chip has been reported to range between 62-100%(4).

The liquid biopsy chip is also more advanced than microfluidics for several reasons. Firstly, the nanotube-chip arrays can capture as well as detect cancer cells, while microfluidics can only capture(4). Samples do not need to be processed for labeling or fixation, so the cell structures are preserved(4). Unlike microfluidics, these nanotubes will also capture tiny structures called exosomes spanning the nanometer range that are produced from cancer cells and carry the same biomarkers(4).

Pancreatic cancer is the fourth leading cause of cancer-associated deaths in the United states, with a survival window of 5 years in only 6% of the cases with treatment(5). In most patients, the disease has already metastasized at the time of diagnosis due to the lack of early-diagnostic markers, affecting some of the major organs such as liver, lungs and the peritoneum(5,6). Despite surgical resection of the primary tumor, the recurrence of local and metastatic tumors is rampant(5). Metastasis is the major cause of mortality in cancers(5). The liquid biopsy chip, that identifies CTCs can thus become an effective diagnostic tool in early detection of cancer as well as provide information into the efficacy of treatment(3). At present, ongoing experiments with this device involve testing for breast cancers but Dr. Balaji Panchapakesan and his team of engineers at WPI are optimistic about incorporating pancreatic and lung cancers into their research.

REFERENCES

1.Nanophenotype. Researchers build liquid biopsy chip that detects metastatic cancer cells in blood: One blood sample can be tested for a comprehensive array of cancer cell biomarkers. 27 Dec 2016. Genesis Nanotechnology,Inc

https://genesisnanotech.wordpress.com/2016/12/27/researchers-build-liquid-biopsy-chip-that-detects-metastatic-cancer-cells-in-blood-one-blood-sample-can-be-tested-for-a-comprehensive-array-of-cancer-cell-markers/

2.Martin TA, Ye L, Sanders AJ, et al. Cancer Invasion and Metastasis: Molecular and Cellular Perspective. In: Madame Curie Bioscience Database [Internet]. Austin (TX): Landes Bioscience; 2000-2013.

https://www.ncbi.nlm.nih.gov/books/NBK164700/

3.F Khosravi, B King, S Rai, G Kloecker, E Wickstrom, B Panchapakesan. Nanotube devices for digital profiling of cancer biomarkers and circulating tumor cells. 23 Dec 2013. IEEE Nanotechnology Magazine 7 (4), 20-26

Nanotube devices for digital profiling of cancer biomarkers and circulating tumor cells

4.Farhad Khosravi, Patrick J Trainor, Christopher Lambert, Goetz Kloecker, Eric Wickstrom, Shesh N Rai and Balaji Panchapakesan. Static micro-array isolation, dynamic time series classification, capture and enumeration of spiked breast cancer cells in blood: the nanotube–CTC chip. 29 Sept 2016. Nanotechnology. Vol 27, No.44. IOP Publishing Ltd

http://iopscience.iop.org/article/10.1088/0957-4484/27/44/44LT03/meta

5.Seyfried, T. N., & Huysentruyt, L. C. (2013). On the Origin of Cancer Metastasis. Critical Reviews in Oncogenesis18(1-2), 43–73.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3597235/

6.Deeb, A., Haque, S.-U., & Olowoure, O. (2015). Pulmonary metastases in pancreatic cancer, is there a survival influence? Journal of Gastrointestinal Oncology6(3), E48–E51. http://doi.org/10.3978/j.issn.2078-6891.2014.114

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4397254/

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

 

Liquid Biopsy Chip detects an array of metastatic cancer cell markers in blood – R&D @Worcester Polytechnic Institute, Micro and Nanotechnology Lab

Reporters: Tilda Barliya, PhD and Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/12/28/liquid-biopsy-chip-detects-an-array-of-metastatic-cancer-cell-markers-in-blood-rd-worcester-polytechnic-institute-micro-and-nanotechnology-lab/

 

Trovagene’s ctDNA Liquid Biopsy urine and blood tests to be used in Monitoring and Early Detection of Pancreatic Cancer

Reporters: David Orchard-Webb, PhD and Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/07/06/trovagenes-ctdna-liquide-biopsy-urine-and-blood-tests-to-be-used-in-monitoring-and-early-detection-of-pancreatic-cancer/

 

Liquid Biopsy Assay May Predict Drug Resistance

Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2015/11/06/liquid-biopsy-assay-may-predict-drug-resistance/


New insights in cancer, cancer immunogenesis and circulating cancer cells

Larry H. Bernstein, MD, FCAP, Curator

https://pharmaceuticalintelligence.com/2016/04/15/new-insights-in-cancer-cancer-immunogenesis-and-circulating-cancer-cells/

 

Prognostic biomarker for NSCLC and Cancer Metastasis

Larry H. Bernstein, MD, FCAP, Curato

https://pharmaceuticalintelligence.com/2016/03/24/prognostic-biomarker-for-nsclc-and-cancer-metastasis/

 

Monitoring AML with “cell specific” blood test

Larry H. Bernstein, MD, FCAP, Curator

https://pharmaceuticalintelligence.com/2016/01/23/monitoring-aml-with-cell-specific-blood-test/

 

Diagnostic Revelations

Larry H. Bernstein, MD, FCAP, Curator

https://pharmaceuticalintelligence.com/2015/11/02/diagnostic-revelations/

 

Circulating Biomarkers World Congress, March 23-24, 2015, Boston: Exosomes, Microvesicles, Circulating DNA, Circulating RNA, Circulating Tumor Cells, Sample Preparation

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2015/03/03/circulating-biomarkers-world-congress-march-23-24-2015-boston-exosomes-microvesicles-circulating-dna-circulating-rna-circulating-tumor-cells-sample-preparation/

 

 

 

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SBI’s Exosome Research Technologies

Reporter: Aviva Lev-Ari, PhD, RN

Welcome to the Fascinating World of Exosomes and Microvesicles

Just learning about exosomes?

The team at SBI has put together this brief overview to help get you started in the growing field of exosome research.

 

Why are exosomes important?

Once thought to be little more than a way for cells to offload waste, the past decade has seen a huge shift in the way we think about exosomes. We’ve begun to recognize that exosomes are deliberately released from the cell, functioning as signal carriers and tissue reshapers through their cargo of RNA, proteins, lipids, and DNA. Involved in a wide range of healthy and pathogenic processes such as cancer, inflammation, immunity, CNS function, cardiac cell function, to name a few – exosomes are being studied for their role in these basic biological processes as well as for their use as biomarkers (see Applications) and even as tools for targeted delivery of biomolecules such as therapeutics (see Engineering).

What are exosomes?

Exosomes are 60 – 180 nm membrane vesicles secreted by most cell types in vivo and in vitro. These extracellular vesicles are endocytic in origin, produced by the inward budding of multivesicular bodies (MVBs). They are released from the cell into the microenvironment following fusion of MVBs with the plasma membrane.

What aren’t exosomes?

Exosomes are not the only small, membrane-bound extracellular vesicle that can be found. They are distinct in origin from apoptotic blebs or apoptotic bodies, which are 50 nm to 5 um in size, carry DNA, RNA, and histones, and display surface markers targeting them for clearance by macrophages. And they are also different from microparticles (also known as microvesicles, ectosomes, shedding vesicles, microparticles, plasma membrane-derived vesicles, and exovesicles), which can range from 50-1000 nm in size and are derived directly from the plasma membrane rather than endocytic bodies within the cell.8 These distinctions and labeling conventions are not always used consistently in the literature and between different groups, leading to some ambiguity in the literature. When isolating exosomes, it’s important to remember that these other types of vesicles may also be present and interpret results accordingly.

What else are exosomes called?

Adding to the confusion, exosomes are sometimes referred to by the source of the sample material. For example, dendritic cell exosomes are also called dexosomes, and cancer cell exosomes may be called oncosomes. Researchers are starting to move towards more standardized nomenclature, but those searching through older literature should be aware of other names for exosomes.

Where are exosomes normally found?

Exosomes have been found in blood, urine, amniotic fluid, breast milk, malignant ascites fluids, and seminal fluid. They contain distinct subsets of molecules depending upon the cell type from which they are secreted, making them useful for biomarker discovery.

How do I study exosomes?

SBI is the only vendor to offer reagents and kits that support all apsects of exosome research-covering isolation, detection and measurement, discovery (characterization and analysis), and even exosome engineering. With a comprehensive set of tools and services to accelerate the study of exosomes and exosome RNA biomarkers, SBI puts the power of exosomes into researchers’ hands.

SBI’s Exosome Research Technologies

ISOLATION

DETECTION

DISCOVERY

ENGINEERING

ExoQuick

Exosome FACS

Purified exosomes

Package miRNAs into exosomes

Exosome FACS and IP

Antibodies and ELISAs

RNA-Seq NGS kit

Transfect exosomes

Exosome depleted FBS

EXOCET assay

Mass Spec library kit

Engineer Exosome Protein Cargo

Label exosome cargo

miRNA qPCR kits

 

SOURCE

https://www.systembio.com/exosome-knowledge

https://www.systembio.com/products

https://www.systembio.com/services

 

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

 

MicroRNAs (miRNAs) are a group of small non-coding RNA molecules that play a major role in posttranscriptional regulation of gene expression and are expressed in an organ-specific manner. One miRNA can potentially regulate the expression of several genes, depending on cell type and differentiation stage. They control every cellular process and their altered regulation is involved in human diseases. miRNAs are differentially expressed in the male and female gonads and have an organ-specific reproductive function. Exerting their affect through germ cells and gonadal somatic cells, miRNAs regulate key proteins necessary for gonad development. The role of miRNAs in the testes is only starting to emerge though they have been shown to be required for adequate spermatogenesis. In the ovary, miRNAs play a fundamental role in follicles’ assembly, growth, differentiation, and ovulation.

 

Deciphering the underlying causes of idiopathic male infertility is one of the main challenges in reproductive medicine. This is especially relevant in infertile patients displaying normal seminal parameters and no urogenital or genetic abnormalities. In these cases, the search for additional sperm biomarkers is of high interest. This study was aimed to determine the implications of the sperm miRNA expression profiles in the reproductive capacity of normozoospermic infertile individuals. The expression levels of 736 miRNAs were evaluated in spermatozoa from normozoospermic infertile males and normozoospermic fertile males analyzed under the same conditions. 57 miRNAs were differentially expressed between populations; 20 of them was regulated by a host gene promoter that in three cases comprised genes involved in fertility. The predicted targets of the differentially expressed miRNAs unveiled a significant enrichment of biological processes related to embryonic morphogenesis and chromatin modification. Normozoospermic infertile individuals exhibit a specific sperm miRNA expression profile clearly differentiated from normozoospermic fertile individuals. This miRNA cargo has potential implications in the individuals’ reproductive competence.

 

Circulating or “extracellular” miRNAs detected in biological fluids, could be used as potential diagnostic and prognostic biomarkers of several disease, such as cancer, gynecological and pregnancy disorders. However, their contributions in female infertility and in vitro fertilization (IVF) remain unknown. Polycystic ovary syndrome (PCOS) is a frequent endocrine disorder in women. PCOS is associated with altered features of androgen metabolism, increased insulin resistance and impaired fertility. Furthermore, PCOS, being a syndrome diagnosis, is heterogeneous and characterized by polycystic ovaries, chronic anovulation and evidence of hyperandrogenism, as well as being associated with chronic low-grade inflammation and an increased life time risk of type 2 diabetes. Altered miRNA levels have been associated with diabetes, insulin resistance, inflammation and various cancers. Studies have shown that circulating miRNAs are present in whole blood, serum, plasma and the follicular fluid of PCOS patients and that these might serve as potential biomarkers and a new approach for the diagnosis of PCOS. Presence of miRNA in mammalian follicular fluid has been demonstrated to be enclosed within microvesicles and exosomes or they can also be associated to protein complexes. The presence of microvesicles and exosomes carrying microRNAs in follicular fluid could represent an alternative mechanism of autocrine and paracrine communication inside the ovarian follicle. The investigation of the expression profiles of five circulating miRNAs (let-7b, miR-29a, miR-30a, miR-140 and miR-320a) in human follicular fluid from women with normal ovarian reserve and with polycystic ovary syndrome (PCOS) and their ability to predict IVF outcomes showed that these miRNAs could provide new helpful biomarkers to facilitate personalized medical care for oocyte quality in ART (Assisted Reproductive Treatment) and during IVF (In Vitro Fertilization).

 

References:

 

http://link.springer.com/chapter/10.1007%2F978-3-319-31973-5_12

 

http://onlinelibrary.wiley.com/doi/10.1111/andr.12276/abstract;jsessionid=F805A89DCC94BDBD42D6D60C40AD4AB0.f03t03

 

http://www.sciencedirect.com/science/article/pii/S0009279716302241

 

http://link.springer.com/article/10.1007%2Fs10815-016-0657-9

 

http://www.nature.com/articles/srep24976

 

 

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Postmarketing Safety or Effectiveness Data Needed: The 2013 paper was funded by the firm Sarepta Therapeutics, sellers of eteplirsen, a surge in its shares seen after the approval. Eteplirsen will cost patients around $300,000 a year.

 

Curator: Aviva Lev-Ari, PhD, RN

 

UPDATED on 8/18/2019

Sarepta Duchenne drug rejected by FDA in surprise setback

 

Dive Brief:

  • In an unexpected decision, the Food and Drug Administration rejected Sarepta Therapeutics’ experimental drug for Duchenne muscular dystrophy, issuing on Monday a Complete Response Letter to the rare disease biotech.
  • According to Sarepta, the agency cited in its refusal infection risk tied to the drug’s delivery as well as preclinical signs of kidney toxicity. Called Vyondys 53, the medicine is designed for roughly 8% of Duchenne patients with a specific genetic mutation.
  • Shares in Cambridge, Mass.-based Sarepta fell sharply in post-market trading. Approval of the drug was widely anticipated, making the rejection a setback in Sarepta’s ambitions to treat a wider pool of Duchenne patients.

SOURCE

https://www.biopharmadive.com/news/sarepta-surprise-fda-rejection-duchenne-vyondys-53/561200/

 

On September 19, the FDA okayed eteplirsen to treat Duchenne muscular dystrophy (DMD), a rare genetic disorder that results in muscle degeneration and premature death. Several of its top officials disagreed with the drug’s approval, questioning how beneficial it will be for patients, as ForbesMedPage Today and others reported.

http://retractionwatch.com/2016/09/21/amid-controversial-sarepta-approval-decision-fda-head-calls-for-key-study-retraction/

Factors at play for FDA Approval of eteplirsen

  1. the help of the families of young boys with Duchenne muscular dystrophy, emotional scenes from these families who have campaigned for so long
  2. an executive team from Sarepta who wouldn’t give up,

Ed Kaye, Sarepta, CEO – EK: It’s all about resilience. One of the things we’ve had is a group of people of like minds and anytime one of us gets down, somebody else is there to pick you up. One of the things we’ve always done is: Every time we’ve felt sorry for ourselves, we just need to think about those patients and what they go through. Our struggles in comparison very quickly become meaningless. You end up saying to yourself: What am I complaining about? Quit whining; get up and do your job.

and

3. an emerging new philosophy from some within the FDA, eteplirsen, now Exondys 51, was approved in patients with a confirmed mutation of the dystrophin gene amenable to exon 51 skipping.

http://www.fiercebiotech.com/biotech/sarepta-ceo-ed-kaye-fda-courage-nice-and-resilience?utm_medium=nl&utm_source=internal&mrkid=993697&mkt_tok=eyJpIjoiTXpBeU56aGpNREV3T1RZMiIsInQiOiJIM2poTkVOQ0N6YmxaenVHZDM1RlVvbTFmRkdwZGdxQ0pmYXNVOG5PKzRyenFXTkRMV0dcL3l0bVBPNkJ2NFV3Rnc3bWVFVnUwMCs3YVhWeVhvRkkrUU5FMFJ1RndSQTlHWFRnQmFTbUo3ODg9In0%3D

9/19/2016

FDA grants accelerated approval to first drug for Duchenne muscular dystrophy

The accelerated approval of Exondys 51 is based on the surrogate endpoint of dystrophin increase in skeletal muscle observed in some Exondys 51-treated patients. The FDA has concluded that the data submitted by the applicant demonstrated an increase in dystrophin production that is reasonably likely to predict clinical benefit in some patients with DMD who have a confirmed mutation of the dystrophin gene amenable to exon 51 skipping. A clinical benefit of Exondys 51, including improved motor function, has not been established. In making this decision, the FDA considered the potential risks associated with the drug, the life-threatening and debilitating nature of the disease for these children and the lack of available therapy.

The FDA granted Exondys 51 fast track designation, which is a designation to facilitate the development and expedite the review of drugs that are intended to treat serious conditions and that demonstrate the potential to address an unmet medical need. It was also granted priority review and orphan drug designationPriority review status is granted to applications for drugs that, if approved, would be a significant improvement in safety or effectiveness in the treatment of a serious condition. Orphan drug designation provides incentives such as clinical trial tax credits, user fee waiver and eligibility for orphan drug exclusivity to assist and encourage the development of drugs for rare diseases.

SOURCE

http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm521263.htm

The viability of this drug approval depends  on “to be gathered” Postmarketing safety or effectiveness data, aka follow-up confirmatory trials.

Sarepta CEO Ed Kaye on FDA courage, NICE and resilience

BA: When it comes to flexibility, however, the FDA will likely not be flexible if your drug doesn’t prove the desired efficacy in your longer term postmarketing studies. If at the end of this period your drug doesn’t come through, how easy will it be for you to take this off the market? I don’t think anyone, including the FDA, wants a repeat of what happened in 2011 when Roche saw its breast cancer license for Avastin, which had been approved under an accelerated review, pulled after not being safe or effective enough in the follow-up confirmatory trials. But you face this as a possible scenario.

EK: That’s true, but one of the things we’re trying to do to mitigate that is to obviously, with our ongoing studies, prove the efficacy that the FDA wants to see. And you know, if there is a problem with one study then we’d hope to have other data that are supportive. The other thing we’re doing of course is developing that next-generation chemistry in DMD that could prove more effective, so we could certainly consider using that next-gen chemistry to take our work forward and try and make it better.

We have a lot of shots on goal to make sure we can continue to supply a product for these boys, but there is always a risk. If we can’t show efficacy in the way the FDA wants, then yes they have the option to take it off the market.

http://www.fiercebiotech.com/biotech/sarepta-ceo-ed-kaye-fda-courage-nice-and-resilience?utm_medium=nl&utm_source=internal&mrkid=993697&mkt_tok=eyJpIjoiTXpBeU56aGpNREV3T1RZMiIsInQiOiJIM2poTkVOQ0N6YmxaenVHZDM1RlVvbTFmRkdwZGdxQ0pmYXNVOG5PKzRyenFXTkRMV0dcL3l0bVBPNkJ2NFV3Rnc3bWVFVnUwMCs3YVhWeVhvRkkrUU5FMFJ1RndSQTlHWFRnQmFTbUo3ODg9In0%3D

Need for follow-up confirmatory trials remains outstanding

FDA’s Postmarketing Surveillance Programs

http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/ucm090385.htm

FDA’s Regulations and Policies and Procedures for Postmarketing Surveillance Programs

http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/ucm090394.htm

 

Positions on Sarepta’s eteplirsen Scientific Approach

Gene Editing for Exon 51: Why CRISPR Snipping might be better than Exon Skipping for DMD

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/01/23/gene-editing-for-exon-51-why-crispr-snipping-might-be-better-than-exon-skipping-for-dmd/

 

QUOTE START

Retraction Watch

Tracking retractions as a window into the scientific process

Amid controversial Sarepta approval decision, FDA head calls for key study retraction

with one comment

FDAThe head of the U.S. Food and Drug Administration (FDA) has called for the retraction of a study about a drug that the agency itself approved earlier this week, despite senior staff opposing the approval.

On September 19, the FDA okayed eteplirsen to treat Duchenne muscular dystrophy (DMD), a rare genetic disorder that results in muscle degeneration and premature death. Several of its top officials disagreed with the drug’s approval, questioning how beneficial it will be for patients, as ForbesMedPage Today and others reported.

In a lengthy report Commissioner Robert Califf sent to senior FDA officials on September 16 — that was made public on September 19 — he called for the retraction of a 2013 study published in Annals of Neurologyfunded by the seller of eteplirsen, which showed beneficial effects of the drug in DMD patients. Califf writes inthe report:

The publication, now known to be misleading, should probably be retracted by its authors.

In a footnote in the report, Califf adds:

In view of the scientific deficiencies identified in this analysis, I believe it would be appropriate to initiate a dialogue that would lead to a formal correction or retraction (as appropriate) of the published report.

The study was not the key factor in the agency’s decision to approve the drug, according to Steve Usdin, Washington editor of the publication BioCentury; still, Usdin told Retraction Watch he is “really surprised” at the call for retraction from top FDA staff, the first he has come across in the last two decades.

The 2013 paper was funded by the firm Sarepta Therapeutics, sellers of eteplirsen, which has seen a surge in its shares after the approval. Eteplirsen will cost patients around $300,000 a year.

DMD affects around 1 in 3,600 boys due to a mutation in the gene that codes for the protein dystrophin, which is important for structural stability of muscles. Eteplirsen is the first drug to treat DMD, and was initially given a green light by Janet Woodcock, director of Center for Drug Evaluation and Research, after a split vote from the FDA’s advisory committee. Despite Califf’s issues with the literature supporting the drug’s use in DMD, he did not overturn Woodcock’s decision, and the agency approved the drug this week.

In 2014, an inspection team visited the Nationwide Children’s Hospital in Columbus, Ohio, where the research was conducted, according to the report. In the report, Ellis Unger, director of the Office of Drug Evaluation I in FDA’s Center for Drug Evaluation, notes:

We found the analytical procedures to be typical of an academic research center, seemingly appropriate for what was simply an exploratory phase 1/2 study, but not suitable for an adequate and well controlled study aimed to serve as the basis for a regulatory action. The procedures and controls that one would expect to see in support of a phase 3 registrational trial were not in evidence.

Specifically, Unger describes concerns about blinding during the experiments, and notes:

The immunohistochemistry images were only faintly stained, and had been read by a single technician using an older liquid crystal display (LCD) computer monitor in a windowed room where lighting was not controlled. (The technician had to suspend reading around mid-day, when brighter light began to fill the room and reading became impossible.)

Unger adds:

Having uncovered numerous technical and operational shortcomings in Columbus, our team worked collaboratively with the applicant to develop improved methods for a reassessment of the stored images…This re-analysis, along with the study published in 2013, provides an instructive example of an investigation with extraordinary results that could not be verified.

Luciana Borio, acting chief scientist at the FDA, is cited in the report saying:

I would be remiss if I did not note that the sponsor has exhibited serious irresponsibility by playing a role in publishing and promoting selective data during the development of this product. Not only was there a misleading published article with respect to the results of Study–which has never been retracted—but Sarepta also issued a press release relying on the misleading article and its findings…As determined by the review team, and as acknowledged by Dr. Woodcock, the article’s scientific findings—with respect to the demonstrated effect of eteplirsen on both surrogate and clinical endpoints—do not withstand proper and objective analyses of the data. Sarepta’s misleading communications led to unrealistic expectations and hope for DMD patients and their families.

Here’s how Sarepta describes the study’s findings in the press release Borio refers to:

Published study results showed that once-weekly treatment with eteplirsen resulted in a statistically significant increase from baseline in novel dystrophin, the protein that is lacking in patients with DMD. In addition, eteplirsen-treated patients evaluable on the 6-minute walk test (6MWT) demonstrated stabilization in walking ability compared to a placebo/delayed-treatment cohort. Eteplirsen was well tolerated in the study with no clinically significant treatment-related adverse events. These data will form the basis of a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for eteplirsen planned for the first half of 2014.

However, Usdin noted that the drug’s approval and the study are two independent events, adding that the 2013 study just “got the ball rolling” for eteplirsen, and the FDA conducted many of its own experiments analyses, as detailed in the newly released report.

Jerry Mendell, the corresponding author of the study (which has so far been cited 118 times, according to Thomson Reuters Web of Science) from Ohio State University in Columbus, told us the allegations were “unfounded” and said the data are “valid.” Therefore, he added, he will not be approaching the journal for a retraction, noting that the FDA asked him hundreds of questions about the paper and audited the trials.

Clifford Saper, the editor-in-chief of Annals of Neurology from the Beth Israel Deaconess Medical Center (which is part of Harvard Medical School), said in an email:

It takes more than a call by a politician for retraction of a paper. It takes actual evidence.

He added:

If the FDA commissioner has, or knows of someone who has, evidence for an error in a paper published in Annals of Neurology, I encourage him to send that evidence to me and a copy to the authors of the article, for their reply. At that point we will engage in a scientific review of the evidence and make appropriate responses.

Linda Lowes, sixth author of the present study, is the last author of a 2016 study in Physical Therapy that was retracted months after publication. Its notice reads:

This article has been retracted by the author due to unintentional deviations in the use of the described modified technique to assess plagiocephaly in the study participants, such that the use of the modified technique cannot be defended for the stated purpose in this population at this time.

Califf was a cardiologist at Duke University during the high-profile scandal of researcher Anil Potti at Duke, which led to more than 10 retractions, settled lawsuits, and medical board reprimands. In 2015, he told TheTriangle Business Journal:

I wish I had gotten myself more involved earlier…There were systems that were not adequate, as we stated. … That was a tough one, I think, for the whole institution.

We’ve contacted the FDA for comment, and will update the post with anything else we learn.

END QUOTE

Correction 9/21/16 10:44 p.m. eastern: When originally published, this post incorrectly reported that Califf was part of an inspection team that visited the Nationwide Children’s Hospital in Ohio, and attributed quotes from Ellis Unger to Califf. We have made appropriate corrections, and apologize for the error.

Like Retraction Watch? Consider making a tax-deductible contribution to support our growth. You can also follow us on Twitter, like us on Facebook, add us to your RSS reader, sign up on our homepage for an email every time there’s a new post, or subscribe to our daily digest. Click here to review our Comments Policy. For a sneak peek at what we’re working on, click here.

SOURCE

http://retractionwatch.com/2016/09/21/amid-controversial-sarepta-approval-decision-fda-head-calls-for-key-study-retraction/

Related Resources on FDA’s Policies on Drugs:

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Exome Aggregation Consortium (ExAC), generated the largest catalogue so far of variation in human protein-coding regions: Sequence data of 60,000 people, NOW is a publicly accessible database

Reporter: Aviva Lev-Ari, PhD, RN

 

UPDATED on 8/22/2016

“The ExAC resource gives us incredible insight when evaluating a patient’s genome sequence in the clinic,” said Heidi Rehm, HMS associate professor of pathology at Brigham and Women’s Hospital, medical clinical director of the Broad’s Clinical Research Sequencing Platform and chief laboratory director of the Laboratory for Molecular Medicine at Partners HealthCare Personalized Medicine.

“In our own research, using the ExAC resource has allowed us to apply novel statistical methods to identify several new severe developmental disorders,” said Matthew Hurles, a researcher at the Wellcome Trust Sanger Institute and frequent user of the ExAC database. “Resources such as ExAC exemplify the benefits that can be achieved for families coping with rare genetic diseases, as a result of the mass altruism of many research participants who allow their data to be aggregated and shared.”

SOURCE

http://hms.harvard.edu/news/going-wide-and-deep?utm_source=Silverpop&utm_medium=email&utm_content=s3&utm_campaign=08.22.16.HMS

 

These variant data already guide diagnoses and treatment

E. V. Minikel et al. Sci. Transl. Med. 8, 322ra9; 2016

Quantifying prion disease penetrance using large population control cohorts

Science Translational Medicine  20 Jan 2016:
Vol. 8, Issue 322, pp. 322ra9
DOI: 10.1126/scitranslmed.aad5169

and

R. Walsh et al. Genet. Med. http://dx.doi.org/10.1038/gim.2016.90; 2016).

Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples

Genetics in Medicine
(2016)
doi:10.1038/gim.2016.90
Published online
17 August 2016

The ExAC project plans to grow over the next year to include 120,000 exome and 20,000 whole-genome sequences. It relies on the willingness of large research consortia to cooperate, and highlights the huge value of sharing, aggregation and harmonization of genomic data. This is also true for patient variants — there is a need for databases that provide greater confidence in variant interpretation, such as the US National Center for Biotechnology Information’s ClinVar database.

SOURCE

Nature536,249(18 August 2016)doi:10.1038/536249a

Read Full Post »


DISCUSSION – Genomics-driven personalized medicine for Pancreatic Cancer, 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)

DISCUSSION – Genomics-driven personalized medicine for Pancreatic Cancer

Reporter: Aviva Lev-Ari, PhD, RN

[bold face added, ALA]

Integrated Patient-Derived Models Delineate Individualized Therapeutic Vulnerabilities of Pancreatic Cancer –>>> Personalized Tumor Models Could Help Identify Combination Therapies for Hard-to-Treat Cancers

 

Original article

Pancreatic Cancer – Genomics-driven personalized medicine

 

PDAC has a particularly poor prognosis, and even with new targeted therapies and chemotherapy, the survival is poor. Here, we show that patient-derived models can be developed and used to investigate therapeutic sensitivities determined by genetic features of the disease and to identify empirical therapeutic vulnerabilities. These data reveal several key points that are of prime relevance to pancreatic cancer and tumor biology in general.

The Challenges of Using Genetic Analysis to Inform Treatment in PDAC

Precision oncology is dependent on the existence of known vulnerabilities encoded by high-potency genetic events and drugs capable of exploiting these vulnerabilities. At present, the repertoire of actionable genetic events in PDAC is limited.

  • Rare BRAF V600E mutations are identified in PDAC and could represent the basis for targeted inhibition, as our group and others have previously published (Collisson et al., 2012; Witkiewicz et al., 2015).

Similarly,

  • germline BRCA deficiency is the basis for ongoing poly(ADP-ribose) polymerase (PARP) inhibitor clinical trials (Lowery et al., 2011).

As shown here, out of 28 cases, only one genetic event was identified that yielded sensitivity to a therapeutic strategy. In this case, existence of the matched model allowed us to confirm the biological relevance of the

  • STAG2 mutation by showing sensitivity of the model to a DNA cross-linking agent.

Therefore, annotated patient-derived models provide a substrate upon which to functionally dissect the significance of novel and potentially actionable genetic events that occur within a tumor.

Another challenge of genomics-driven personalized medicine is

  • assessing the effect of specific molecular aberrations on therapeutic response in the context of complex genetic changes present in individual tumors.
  • KRAS has been proposed to modify therapeutic dependency to EZH2 inhibitors (Kim et al., 2015), and in the models tested, responses to this class of drugs were not uniformly present in cases harboring mutations in chromatin-remodeling genes.

This finding suggests that, although tumors acquire genetic alterations in specific genes, the implicated pathway may not be functionally inactive or therapeutically actionable. Therefore, annotated patient derived models provide a unique test bed for interrogating specific therapeutic dependencies in a genetically tractable system.

Empirical Definition of Therapeutic Sensitivities and Clinical Relevance

Cell lines offer the advantage of the ability to conduct high throughput approaches to interrogate many therapeutic agents. A large number of failed clinical trials have demonstrated the difficulty in treating PDAC. Based on the data herein, the paucity of clinical success is, most probably, due to the diverse therapeutic sensitivity of individual PDAC cases, suggesting that, with an unselected patient population, it will be veritably impossible to demonstrate clinical benefit. Additionally,

  •  very few models exhibited an exceptional response to single agents across the breadth of a library encompassing 305 agents.
  • We could identify only one tumor that was particularly sensitive to MEK inhibition and another model that was sensitive to
  • EGFR and
  • tyrosine kinase inhibitors.

In contrast to the limited activity of single agents, combination screens yielded responses at low-dose concentrations in the majority of models. Specific combinations were effective across several models, indicating that, by potentially screening more models, therapeutic sensitivity clades of PDAC will emerge. In the pharmacological screens performed in this study,

  • MEK inhibition, coupled with MTOR, docetaxel, or tyrosine kinase inhibitors, was effective in _30% of models tested.
  • Resistance to MEK inhibitors occurs through several mechanisms, including
  • Upregulation of oncogenic bypass signaling pathways such as AKT, tyrosine kinase, or MTOR (mammalian target of rapamycin) signaling.

In the clinic, the MEK and MTOR inhibitors (e.g., NCT02583542) are being tested. An intriguing finding from the drug screen was

  • sensitivity of a subset of models to combined MEK and docetaxel inhibition. This combination has been observed to synergistically enhance apoptosis and inhibit tumor growth in human xenograft tumor models (Balko et al., 2012; McDaid et al., 2005) and is currently being tested in a phase III study in patients with KRAS-mutated, advanced non-small-cell lung adenocarcinoma (Ja¨ nne et al., 2016).

Interestingly, in the models tested herein, there was limited sensitivity imparted through

  •  the combination of gemcitabine and MEK inhibition.

This potentially explains why the combination of MEK inhibitor and gemcitabine tested in the clinic did not show improved efficacy over gemcitabine alone (Infante et al., 2014).

Another promising strategy that emerged from this study involves using

  • CHK or BCL2 inhibitors as agents that drive enhanced sensitivity to chemotherapy.

Together, the data suggest that the majority of PDAC tumors have intrinsic therapeutic sensitivities, but the challenge is to prospectively identify effective treatment.

Patient-Derived Model-Based Approach to Precision Medicine

This study supports a path for guiding patient treatment based on the integration of genetic and empirically determined sensitivities of the patient’s tumor (Figure S7). In reference to defined genetic susceptibilities, the models provide a means to interrogate the voracity of specific drug targets. Parallel unbiased screening enables the discovery of sensitivities that could be exploited in the clinic. The model-guided treatment must be optimized, allowing for the generation of data in a time frame compatible with clinical decision making and appropriate validation.

In the present study, the majority of models were developed, cell lines were drug screened, and select hits were validated in PDX models within a 10- to 12-month window (Figure S7). This chronology would allow time to inform frontline therapy for recurrent disease for most patients who were surgically resected and treated with a standard of care where the median time to recurrence is approximately 14 months (Saif, 2013).

Although most models were generated from surgically resected specimens, two of the models (EMC3226 and EMC62) were established from primary tumor biopsies, indicating that this approach could be used with only a limited amount of tumor tissue available.

In the context of inoperable pancreatic cancer, application of data from a cell-line screen without in vivo validation in PDX would permit the generation of sensitivity data in the time frame compatible with treatment.

[We] acknowledge that model-guided treatment is also not without significant logistical hurdles, including the availability of drugs for patient treatment, clinically relevant time frames, patient-performance status, toxicity of combination regiments, and quality metrics related to model development and therapeutic response evaluation.

Additionally, it will be very important to monitor ex vivo genetic and phenotypic divergence with passage and try to understand the features of tumor heterogeneity that could undermine the efficacy of using models to direct treatment. As shown here, drug sensitivities remained stable with passage in cell culture and, importantly, were confirmed in PDX models, suggesting that the dominant genetic drivers and related therapeutic sensitivities are conserved.

In spite of these challenges, progressively more effort is going into the development of patient-derived models for guidance of disease treatment (Aparicio et al., 2015; Boj et al., 2015; Crystal et al., 2014; van de Wetering et al., 2015).

Several ongoing trials use PDX models to direct a limited repertoire of agents (e.g., NCT02312245, NCT02720796, and ERCAVATAR2015). Given the experience here, PDAC cell lines would provide the opportunity to rapidly interrogate a larger portfolio of combinations that could be used to guide patient care and provide a novel approach to precision medicine.

Validation of this approach would require the establishment of challenging multi-arm or N-of-1 clinical trials. However, considering the dire outcome for PDAC patients and the long-lasting difficulty in developing effective treatments, this non-canonical approach might be particularly impactful in pancreatic cancer.

SOURCE

Witkiewicz et al., 2016, Cell Reports 16, 1–15

August 16, 2016 ª 2016 The Author(s).

http://dx.doi.org/10.1016/j.celrep.2016.07.023

Agnieszka K. WitkiewiczPress enter key for correspondence information
Uthra Balaji
Cody Eslinger
Elizabeth McMillan
William Conway
Bruce Posner
Gordon B. Mills
Eileen M. O’Reilly
Erik S. KnudsencorrespondencePress enter key for correspondence information
Publication stage: In Press Corrected Proof
Open Access

Resource Integrated Patient-Derived Models Delineate Individualized Therapeutic Vulnerabilities of Pancreatic Cancer

Correspondence

awitki@email.arizona.edu (A.K.W.),

eknudsen@email.arizona.edu (E.S.K.)

Accession Numbers: GSE84023

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

Pancreatic Cancer: Articles of Note @PharmaceuticalIntelligence.com

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/05/26/pancreatic-cancer-articles-of-note-pharmaceuticalintelligence-com/

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Crowdsourcing Genetic Data Yields Discovery of DNA loci associated with Major Depressive Disorder (MDD) in European Descendants, 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)

Crowdsourcing Genetic Data Yields Discovery of DNA loci associated with Major Depressive Disorder (MDD) in European Descendants

 

Reporter: Kelly Perlman, Life Sciences Student and Research Assistant, McGill University

 

UPDATED on 11/24/2019

Can AI help diagnose depression? It’s a long shot

At the moment, machine intelligence is just as subjective as human intelligence

Alejandra Canales

https://www.salon.com/2019/11/23/can-ai-help-diagnose-depression-its-a-long-shot_partner/amp?__twitter_impression=true

Researchers from Pfizer Global Research and Development, 23andMe, and the Massachusetts General Hospital have published a study in Nature Genetics, pinpointing 15 genetic loci associated with the risk of developing major depressive disorder (MDD) in individuals of European ancestry. Evidence from previous research suggests that MDD is heritable, but the details of the specific gene correlates are unclear. The identification of loci where single nucleotide polymorphisms (SNPs) related to MDD exist could provide better insight into the neurobiology of depression, and therefore better treatment options.

23andMe, a private biotechnology company situated in California, offers a DNA sequencing service in which consumers send in a saliva swab for testing, and later receive a report listing the findings of the analysis related to ancestry, physical and behavioral traits, along with risk of inheriting certain diseases. The participants of this study had agreed to provide the results of their genetic testing for scientific research.

The results of 75,607 participants with self-reported diagnoses of depression were compared to the results of 231,747 participants reporting having never experienced depression. This data was combined with the results of previously published MDD genome-wide association studies (GWAS). To test the whether these results could be replicated, another set of results from 23andMe was analyzed, in which there were 45,773 MDD subjects, and 106,354 controls.

After the joint analysis, 17 SNPs were identified at 15 different loci. Tissue and gene enrichment assays showed that the genes that were over-expressed in the CNS were related to functions including neurodevelopment, histone methylation, neurogenesis and synaptic modification.

The team then created a weighted genetic risk score (GRS) in which they compared the 17 SNPs with factors including medication use, comorbid diseases and behavioral phenotypes, all of which were correlated with the GRS. Of note, the GRS was very highly correlated with age of onset of MDD.

The crowdsourcing of genetic data proves to be an efficient and powerful tool for large-scale MDD studies. Pooling large subject databases together is essential in order to account for the heterogeneous nature of the disease. Despite not being able to precisely assess each subject’s disease phenotype, scientists can make more rapid headway by collaborating with biotechnology companies in the quest to better understand the biological mechanisms of depression. Ron Perlis, M.D., M.Sc., of the Massachusetts General Hospital and co-author of this paper explained that “finding genes associated with depression should help make clear that this is a brain disease, which we hope will decrease the stigma still associated with these kinds of illnesses”.

 

Details on specific significant genes:

http://www.genecards.org/cgi-bin/carddisp.pl?gene=OLFM4

http://www.genecards.org/cgi-bin/carddisp.pl?gene=TMEM161B

http://www.genecards.org/cgi-bin/carddisp.pl?gene=MEF2C

http://www.genecards.org/cgi-bin/carddisp.pl?gene=MEIS2

http://www.genecards.org/cgi-bin/carddisp.pl?gene=TMCO5A

http://www.genecards.org/cgi-bin/carddisp.pl?gene=NEGR1

 

SOURCES

Hyde, C. L., Nagle, M. W., Tian, C., Chen, X., Paciga, S. A., Wendland, J. R., . . . Winslow, A. R. (2016). Identification of 15 genetic loci associated with risk of major depression in individuals of European descent. Nature Genetics Nat Genet. doi:10.1038/ng.3623

Major Depressive Disorder Loci Discovered in Large GWAS Enabled by 23andMe Participants’ Data. (2016, August 01). Retrieved August 09, 2016, from https://www.genomeweb.com/microarrays-multiplexing/major-depressive-disorder-loci-discovered-large-gwas-enabled-23andme

 

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Using Online Mendelian Inheritance in Man (OMIM) database and the Human Genome Mutation Database (HGMD) Pro 2015.2 for Quantification of the growth in gene-disease and variant-disease associations, 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)

Using Online Mendelian Inheritance in Man (OMIM) database and the Human Genome Mutation Database (HGMD) Pro 2015.2 for Quantification of the growth in gene-disease and variant-disease associations

Reporter: Aviva Lev-Ari, PhD, RN

 

Reanalysis of Clinical Exome Data Over Time Could Yield New Diagnoses

NEW YORK (GenomeWeb) – Clinical exomes that are re-evaluated in a systematic way could yield new diagnoses and prove useful to clinicians, according to a study published yesterday in Genetics in Medicine.

A team of researchers from Stanford University set out to examine whether nondiagnostic clinical exomes could provide new information for patients if they were re-examined with current bioinformatics software and knowledge of disease-related variants as presented in the literature.

Clinical exome sequencing yields no diagnosis for about 75 percent of patients evaluated for possible Mendelian disorders, wrote senior author Gill Bejerano and his colleagues. But a reanalysis of exome and phenotypic data from 40 such individuals using current methods identified a definitive diagnosis for four of them — 10 percent — the team said.

In these cases, the causative variant was de novo and found in a relevant autosomal-dominant disease gene. At the time these exomes were first sequenced, the researchers wrote, the existing literature on these causative genes was either “weak, nonexistent, or not readily located.” When the exomes were re-examined by his team, Bejerano noted, the supporting literature was more robust.

SOURCE

https://www.genomeweb.com/sequencing/reanalysis-clinical-exome-data-over-time-could-yield-new-diagnoses?utm_source=SilverpopMailing&utm_medium=email&utm_campaign=Daily%20News:%20Reanalysis%20of%20Clinical%20Exome%20Data%20Over%20Time%20Could%20Yield%20New%20Diagnoses%20-%2007/22/2016%2011:20:00%20AM

At ACMG, Researchers Report Data Re-Analysis, Matchmaking Boosts Solved Exome Cases

In addition to re-analyzing exome data, the researchers have been working on establishing causality for novel candidate disease genes through patient matches. For this, the team has been using the GeneMatcher website, which allows them to find other clinicians and researchers around the world who have patients, or animal models, with mutations in the same genes as their own patients. Through an API developed by the Matchmaker Exchange project, GeneMatcher submitters can also query the PhenomeCentral and Decipher databases. As of March, more than 4,000 genes had been submitted to GeneMatcher from more than 1,300 submitters in 48 countries, and 1,900 matches had been made, Sobreira reported.

Her team has so far submitted data from 104 families, involving 280 genes, and has had 314 matches so far, involving 113 genes. Several cases have been successes, meaning the researchers could establish that a candidate gene is indeed disease causing, and several others are pending, both from Hopkins and from other groups. The total number of solved cases tracing their success to GeneMatcher is currently unknown, Sobreira said, but the organizers are planning to survey submitters about their success rate in the near future.

SOURCE

https://www.genomeweb.com/molecular-diagnostics/acmg-researchers-report-data-re-analysis-matchmaking-boosts-solved-exome-cases

 

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