Funding, Deals & Partnerships: BIOLOGICS & MEDICAL DEVICES; BioMed e-Series; Medicine and Life Sciences Scientific Journal – http://PharmaceuticalIntelligence.com
New evidence has shown how coronavirus has caused much damage to the brain. There is a new evidence that shows that COVID-19 assault on the brain I has the power to be multipronged. What this means is that it can attack on certain Brain cells such as reduce the amount of blood flow that the brain needs to the brain tissue.
Along with brain damage COVID-19 has also caused strokes and memory loss. A neurologist at yell University Serena Spudich says, “Can we intervene early to address these abnormalities so that people don’t have long-term problems?”
We’re on 80% of the people who have been hospitalized due to COVID-19 have showed brain symptoms which seem to be correlated to coronavirus.
At the start of the pandemic a group of researchers speculated that coronavirus they can damage the brain by infecting the neurons in the cells which are important in the process of transmitting information. After further studies they found out that coronavirus has a harder time getting past the brains defense system and the brain barrier and that it does not affect the neurons in anyway.
An expert in this study indicated that a way in which SARS-CoV-2 may be able to get to the brain is by going through the olfactory mucosa which is the lining of the nasal cavity. It is found that this virus can be found in the nasal cavity which is why we swab the nose one getting tested for COVID-19.
Spudich quotes, “there’s not a tonne of virus in the brain”.
Recent studies indicate that SARS-CoV-2 have ability to infect astrocytes which is a type of cell found in the brain. Astrocytes do quite a lot that supports normal brain function,” including providing nutrients to neurons to keep them working, says Arnold Kriegstein, a neurologist at the University of California, San Francisco.
Astrocytes are star-shaped cells in the central nervous system that perform many functions, including providing nutrients to neurons.
Kriegstein and his fellow colleagues have found that SARS-CoV-2 I mostly infects the astrocytes over any of the other brain cells present. In this research they expose brain organoids which is a miniature brain that are grown from stem cells into the virus.
As quoted in the article” a group including Daniel Martins-de-Souza, head of proteomics at the University of Campinas in Brazil, reported6 in a February preprint that it had analysed brain samples from 26 people who died with COVID-19. In the five whose brain cells showed evidence of SARS-CoV-2 infection, 66% of the affected cells were astrocytes.”
The infected astrocytes could indicate the reasoning behind some of the neurological symptoms that come with COVID-19. Specifically, depression, brain fog and fatigue. Kreigstein quotes, “Those kinds of symptoms may not be reflective of neuronal damage but could be reflective of dysfunctions of some sort. That could be consistent with astrocyte vulnerability.”
A study that was published on June 21 they compared eight different brands of deceased people who did have COVID-19 along with 14 brains as the control. The results of this research were that they found that there was no trace of coronavirus Brain infected but they found that the gene expression was affected in some of the astrocytes.
As a result of doing all this research and the findings the researchers want to know more about this topic and how many brain cells need to be infected for there to be neurological symptoms says Ricardo Costa.
Further evidence has also been done on how SARS-CoV-2 can affect the brain by reducing its blood flow which impairs the neurons’ function which ends up killing them.
Pericytes can be found on the small blood vessels which are called capillaries and are found all throughout the body and in the brain. In a February pre-print there was a report about how SARS-CoV-2 can infect the pericyte in the brain organoids.
David Atwell, a neuroscientist at the University College London, along with his other colleagues had published a pre-print which has evidence to show that SARS-CoV-2 odes In fact pericytes behavior. I researchers saw that in the different part of the hamsters brain SARS-CoV-2 blocks the function of receptors on the pericytes which ultimately causes the capillaries found inside the tissues to constrict.
As stated in the article, It’s a “really cool” study, says Spudich. “It could be something that is determining some of the permanent injury we see — some of these small- vessel strokes.”
Attwell brought to the attention that the drugs that are used to treat high blood pressure may in fact be used in some cases of COVID-19. Currently there are two clinical trials that are being done to further investigate this idea.
There is further evidence showing that the neurological symptoms and damage could in fact be happening because of the bodies on immune system reacting or misfiring after having COVID-19.
Over the past 15 years it has become evident that people’s immune system’s make auto antibodies which attack their own tissues says Harald Prüss in the article who has a Neuroimmunologist at the German Center for neurogenerative Diseases in Berlin. This may cause neuromyelitis optica which is when you can experience loss of vision or weakness in limbs. Harald Prüss summarized that the autoantibodies can pass through the blood brain barrier and ultimately impact neurological disorders such as psychosis.
Prüss and his colleagues published a study last year that focused on them isolating antibodies against SARS-CoV-2 from people. They found that one was able to protect hamsters from lung damage and other infections. The purpose of this was to come up with and create new treatments. During this research they found that some of the antibodies from people. They found that one was able to protect hamsters from lung damage and other infections. The purpose of this was to come up with and create new treatments. During this research they found that some of the antibodies can bind to the brain tissue which can ultimately damage it. Prüss states, “We’re currently trying to prove that clinically and experimentally,” says Prüss.
Was published online in December including Prüss sorry the blood and cerebrospinal fluid of 11 people who were extremely sick with COVID-19. These 11 people had neurological symptoms as well. All these people were able to produce auto antibodies which combined to neurons. There is evidence that when the patients were given intravenous immunoglobin which is a type of antibody it was successful.
Astrocytes, pericytes and autoantibodies we’re not the only pathways. However it is likely that people with COVID-19 experience article symptoms for many reasons. As stated, In the article, Prüss says a key question is what proportion of cases is caused by each of the pathways. “That will determine treatment,” he says.
Comparing COVID-19 Vaccine Schedule Combinations, or “Com-COV” – First-of-its-Kind Study will explore the Impact of using eight different Combinations of Doses and Dosing Intervals for Different COVID-19 Vaccines
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
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
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
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
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,
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
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
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
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?
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
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
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,
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
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
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
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
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
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
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
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?
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?
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
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?
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.
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
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?
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
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
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?
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
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
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
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
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?
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
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
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.
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
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?
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
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
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:
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
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
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?
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?
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?
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
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
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
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
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
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
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
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
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
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
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
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?
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
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
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:
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
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
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?
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?
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?
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
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
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
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
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
Ear inside the scall compartments and receptors responsible for hearing highly differentiated tall ask to identify cell for anticipated differentiation
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
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
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
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
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:
Bob Carter, MD, PhD Chairman, Department of Neurosurgery, MGH William and Elizabeth Sweet, Professor of Neurosurgery, HMS Neurogeneration REVERSAL or slowing down?
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
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
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
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
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
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
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
Nabiha Saklayen, PhD CEO and Co-Founder, Cellino scale production of autologous cells foundry using semiconductor process in building cassettes by optic physicists
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
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
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
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
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
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
Two brothers with MEPAN Syndrome: A Rare Genetic Disorder
Reporter: Amandeep Kaur
In the early 40s, a married couple named Danny and Nikki, had normal pregnancy and delivered their first child in October 2011. The couple was elated after the birth of Carson because they were uncertain about even conceiving a baby. Soon after birth, the parents started facing difficulty in feeding the newborn and had some wakeful nights, which they used to called “witching hours”. For initial six months, they were clueless that something was not correct with their infant. Shortly, they found issues in moving ability, sitting, and crawling with Carson. Their next half year went in visiting several behavioral specialists and pediatricians with no conclusion other than a suggestion that there is nothing to panic as children grow at different rates.
Later in early 2013, Caron was detected with cerebral palsy in a local regional center. The diagnosis was based on his disability to talk and delay in motor development. At the same time, Carson had his first MRI which showed no negative results. The parents convinced themselves that their child condition would be solved by therapies and thus started physical and occupational therapies. After two years, the couple gave birth to another boy child named Chase in 2013. Initially, there was nothing wrong with Chase as well. But after nine months, Chase was found to possess the same symptoms of delaying in motor development as his elder brother. It was expected that Chase may also be suffering from cerebral palsy. For around one year both boys went through enormous diagnostic tests starting from karyotyping, metabolic screen tests to diagnostic tests for Fragile X syndrome, lysosomal storage disorders, Friedreich ataxia and spinocerebellar ataxia. Gene panel tests for mitochondrial DNA and Oxidative phosphorylation (OXPHOS) deficiencies were also performed. No conclusion was drawn because each diagnostic test showed the negative results.
Over the years, the condition of boys was deteriorating as their movements became stiffer and ataxic, they were not able to crawl anymore. By the end of 2015, the boys had an MRI which showed some symmetric anomalies in their basal ganglia indicating a metabolic condition. The symptoms of Carson and Chase was not even explained by whole exome sequencing due to the absence of any positive result. The grievous journey of visits to neurologist, diagnostic tests and inconclusive results led the parents to rethink about anything happened erroneous due to them such as due to their lifestyle, insufficient intake of vitamins during pregnancy or exposure to toxic agents which left their sons in that situation.
During the diagnostic odyssey, Danny spent many restless and sleepless nights in searching PubMed for any recent cases with symptoms similar to his sons and eventually came across the NIH’s Undiagnosed Diseases Network (UDN), which gave a light of hope to the demoralized family. As soon as Danny discovered about the NIH’s Diseases Network, he gathered all the medical documents of both his sons and submitted the application. The submitted application in late 2015 got accepted a year later in December 2016 and they got their first appointment in early 2017 at the UDN site at Stanford. At Stanford, the boys had gone through whole-genome sequencing and some series of examinations which came back with inconclusive results. Finally, in February 2018, the family received some conclusive results which explained that the two boys suffer from MEPAN syndrome with pathogenic mutations in MECR gene.
MEPAN means Mitochondrial Enoyl CoA reductase Protein-Associated Neurodegeneration
MEPAN syndrome is a rare genetic neurological disorder
MEPAN syndrome is associated with symptoms of ataxia, optic atrophy and dystonia
The wild-type MECR gene encodes a mitochondrial protein which is involved in metabolic processes
The prevalence rate of MEPAN syndrome is 1 in 1 million
Currently, there are 17 patients of MEPAN syndrome worldwide
The symptoms of Carson and Chase of an early onset of motor development with no appropriate biomarkers and T-2 hyperintensity in the basal ganglia were matching with the seven known MEPAN patient at that time. The agonizing journey of five years concluded with diagnosis of rare genetic disorder.
Despite the advances in genetic testing and their low-cost, there are many families which still suffer and left undiagnostic for long years. To shorten the diagnostic journey of undiagnosed patients, the whole-exome and whole-genome sequencing can be used as a primary tool. There is need of more research to find appropriate treatments of genetic disorders and therapies to reduce the suffering of the patients and families. It is necessary to fill the gap between the researchers and clinicians to stimulate the development in diagnosis, treatment and drug development for rare genetic disorders.
The family started a foundation named “MEPAN Foundation” (https://www.mepan. org) to reach out to the world to educate people about the mutation in MECR gene. By creating awareness among the communities, clinicians, and researchers worldwide, the patients having rare genetic disorder can come closer and share their information to improve their condition and quality of life.
Alnylam Announces First-Ever FDA Approval of an RNAi Therapeutic, ONPATTRO™ (patisiran) for the Treatment of the Polyneuropathy of Hereditary Transthyretin-Mediated Amyloidosis in Adults
Dysregulation of ncRNAs in association with Neurodegenerative Disorders
Curator: Amandeep Kaur
Research over the years has added evidences to the hypothesis of “RNA world” which explains the evolution of DNA and protein from a simple RNA molecule. Our understanding of RNA biology has dramatically changed over the last 50 years and rendered the scientists with the conclusion that apart from coding for protein synthesis, RNA also plays an important role in regulation of gene expression.
The universe of non-coding RNAs (ncRNAs) is transcending the margins of preconception and altered the traditional thought that the coding RNAs or messenger RNAs (mRNAs) are more prevalent in our cells. Research on the potential use of ncRNAs in therapeutic relevance increased greatly after the discovery of RNA interference (RNAi) and provided important insights into our further understanding of etiology of complex disorders.
Latest research on neurodegenerative disorders has shown the perturbed expression of ncRNAs which provides the functional association between neurodegeneration and ncRNAs dysfunction. Due to the diversity of functions and abundance of ncRNAs, they are classified into Housekeeping RNAs and Regulatory ncRNAs.
The best known classes of ncRNAs are the microRNAs (miRNAs) which are extensively studied and are of research focus. miRNAs are present in both intronic and exonic regions of matured RNA (mRNA) and are crucial for development of CNS. The reduction of Dicer-1, a miRNA biogenesis-related protein affects neural development and the elimination of Dicer in specifically dopaminergic neurons causes progressive degeneration of these neuronal cells in striatum of mice.
A new class of regulatory ncRNAs, tRNAs-derived fragments (tRFs) is superabundantly present in brain cells. tRFs are considered as risk factors in conditions of neural degeneration because of accumulation with aging. tRFs have heterogenous functions with regulation of gene expression at multiple layers including regulation of mRNA processing and translation, inducing the activity of silencing of target genes, controlling cell growth and differentiation processes.
The existence of long non-coding RNAs (lncRNAs) was comfirmed by the ENCODE project. Numerous studies reported that approximately 40% of lncRNAs are involved in gene expression, imprinting and pluripotency regulation in the CNS. lncRNA H19 is of paramount significance in neural viability and contribute in epilepsy condition by activating glial cells. Other lncRNAs are highly bountiful in neurons including Evf2 and MALAT1 which play important function in regulating neural differentiation and synapse formation and development of dendritic cells respectively.
Recently, a review article in Nature mentioned about the complex mechanisms of ncRNAs contributing to neurodegenerative conditions. The ncRNA-mediated mechanisms of regulation are as follows:
Epigenetic regulation: Various lncRNAs such as BDNF-AS, TUG1, MEG3, NEAT1 and TUNA are differentially expressed in brain tissue and act as epigenetic regulators.
RNAi: RNA interference includes post-transcriptional repression by small-interfering RNAs (siRNAs) and binding of miRNAs to target genes. In a wide spectrum of neurodegenerative diseases such as Alzheimer’s disease, Parkinson disease, Huntington’s disease, Amyotrophic lateral sclerosis, Fragile X syndrome, Frontotemporal dementia, and Spinocerebellar ataxia, have shown perturbed expression of miRNA.
Alternative splicing: Variation in splicing of transcripts of ncRNAs has shown adverse affects in neuropathology of degenerative diseases.
mRNA stability: The stability of mRNA may be affected by RNA-RNA duplex formation which leads to the degradation of sense mRNA or blocking the access to proteins involved in RNA turnover and modify the progression of neurodegenerative disorders.
Translational regulation: Numerous ncRNAs including BC200 directly control the translational process of transcripts of mRNAs and effect human brain of Alzheimer’s disease.
Molecular decoys: Non-coding RNAs (ncRNAs) dilute the expression of other RNAs by molecular trapping, also known as competing endogenous RNAs (ceRNAs) which hinder the normal functioning of RNAs. The ceRNAs proportion must be equivalent to the number of target miRNAs that can be sequestered by each ncRNAs in order to induce consequential de-repression of the target molecules.
The unknown functions of numerous annotated ncRNAs may explain the underlying complexity in neurodegenerative disorders. The profiling of ncRNAs of patients suffering from neurodevelopmental and neurodegenerative conditions are required to outline the changes in ncRNAs and their role in specific regions of brain and cells. Analysis of Large-scale gene expression and functional studies of ncRNAs may contribute to our understanding of these diseases and their remarkable connections. Therefore, targeting ncRNAs may provide effective therapeutic perspective for the treatment of neurodegenerative diseases.
Mechanistic link between SARS-CoV-2 infection and increased risk of stroke using 3D printed models and human endothelial cells
Reporter: Adina Hazan, PhD
Kaneko, et al. from UCLA aimed to explore why SARS-CoV-2 infection is associated with an increased rate of cerebrovascular events, including
ischemic stroke and
intracerebral hemorrhage
While some suggested mechanisms include an overall systemic inflammatory response including increasing circulating cytokines and leading to a prothrombotic state, this may be only a partial answer. A SARS-CoV-2 specific mechanism could be likely, considering that both angiotensin-converting enzyme-2 (ACE2), the receptor necessary for SARS-CoV-2 to gain entry into the cell, and SARS-CoV-2 RNA have been reportedly detected in the human brain postmortem.
One of the difficulties in studying vasculature mechanisms is that the inherent 3D shape and blood flow subject this tissue to different stressors, such as flow, that could be critically relevant during inflammation. To accurately study the effect of SARS-CoV-2 on the vasculature of the brain, the team generated 3D models of the human middle cerebral artery during intracranial artery stenosis using data from CT (computed tomography) angiography. This data was then exported with important factors included such as
shear stress during perfusion,
streamlines, and
flow velocity to be used to fabricate 3D models.
These tubes were then coated with endothelial cells isolated and sorted from normal human brain tissue resected during surgery. In doing so, this model could closely mimic the cellular response of the vasculature of the human brain.
Surprisingly, without this 3D tube, human derived brain endothelial cells displayed very little expression of ACE2 or, TMPRSS2 (transmembrane protease 2), a necessary cofactor for SARS-COV-2 viral entry.
Interestingly,
horizontal shear stress increased the expression of ACE2 and
increased the binding of spike protein to ACE2, especially within the stenotic portion of the 3D model.
By exposing the endothelial cells to liposomes expressing the SARS-CoV-2 spike protein, they also were able to explore key upregulated genes in the exposed cells, in which they found that
“binding of SARS-CoV-2 S protein triggered 83 unique genes in human brain endothelial cells”.
This included many inflammatory signals, some of which have been previously described as associated with SARS-COV-2, and others whose effects are unknown. This may provide an important foundation for exploring potential therapeutic targets in patients susceptible to cerebrovascular events.
Overall, this study shows important links between the
mechanisms of SARS-CoV-2 and the
increase in ischemic events in these patients. It also has important implications for
treatment for SARS-CoV-2, as high blood pressure and atherosclerosis may be increasing ACE2 expression in patients, providing the entry port for viral particles into brain endothelia.
Parkinson’s Disease (PD), characterized by both motor and non-motor system pathology, is a common neurodegenerative disorder affecting about 1% of the population over age 60. Its prevalence presents an increasing social burden as the population ages. Since its introduction in the 1960’s, dopamine (DA)-replacement therapy (e.g., L-DOPA) has remained the gold standard treatment. While improving PD patients’ quality of life, the effects of treatment fade with disease progression and prolonged usage of these medications often (>80%) results in side effects including dyskinesias and motor fluctuations. Since the selective degeneration of A9 mDA neurons (mDANs) in the substantia nigra (SN) is a key pathological feature of the disease and is directly associated with the cardinal motor symptoms, dopaminergic cell transplantation has been proposed as a therapeutic strategy.
Researchers showed that mammalian fibroblasts can be converted into embryonic stem cell (ESC)-like induced pluripotent stem cells (iPSCs) by introducing four transcription factors i.e., Oct4, Sox2, Klf4, and c-Myc. This was then accomplished with human somatic cells, reprogramming them into human iPSCs (hiPSCs), offering the possibility of generating patient-specific stem cells. There are several major barriers to implementation of hiPSC-based cell therapy for PD. First, probably due to the limited understanding of the reprogramming process, wide variability exists between the differentiation potential of individual hiPSC lines. Second, the safety of hiPSC-based cell therapy has yet to be fully established. In particular, since any hiPSCs that remain undifferentiated or bear sub-clonal tumorigenic mutations have neoplastic potential, it is critical to eliminate completely such cells from a therapeutic product.
In the present study the researchers established human induced pluripotent stem cell (hiPSC)-based autologous cell therapy. Researchers reported a platform of core techniques for the production of mDA progenitors as a safe and effective therapeutic product. First, by combining metabolism-regulating microRNAs with reprogramming factors, a method was developed to more efficiently generate clinical grade iPSCs, as evidenced by genomic integrity and unbiased pluripotent potential. Second, a “spotting”-based in vitro differentiation methodology was established to generate functional and healthy mDA cells in a scalable manner. Third, a chemical method was developed that safely eliminates undifferentiated cells from the final product. Dopaminergic cells thus produced can express high levels of characteristic mDA markers, produce and secrete dopamine, and exhibit electrophysiological features typical of mDA cells. Transplantation of these cells into rodent models of PD robustly restored motor dysfunction and reinnervated host brain, while showing no evidence of tumor formation or redistribution of the implanted cells.
Together these results supported the promise of these techniques to provide clinically applicable personalized autologous cell therapy for PD. It was recognized by researchers that this methodology is likely to be more costly in dollars and manpower than techniques using off-the-shelf methods and allogenic cell lines. Nevertheless, the cost for autologous cell therapy may be expected to decrease steadily with technological refinement and automation. Given the significant advantages inherent in a cell source free of ethical concerns and with the potential to obviate the need for immunosuppression, with its attendant costs and dangers, it was proposed that this platform is suitable for the successful implementation of human personalized autologous cell therapy for PD.
Lesson 4 Cell Signaling And Motility: G Proteins, Signal Transduction: Curations and Articles of reference as supplemental information: #TUBiol3373
Curator: Stephen J. Williams, Ph.D.
Updated 7/15/2019
Below please find the link to the Powerpoint presentation for lesson #4 for #TUBiol3373. The lesson first competes the discussion on G Protein Coupled Receptors, including how cells terminate cell signals. Included are mechanisms of receptor desensitization. Please NOTE that desensitization mechanisms like B arrestin decoupling of G proteins and receptor endocytosis occur after REPEATED and HIGH exposures to agonist. Hydrolysis of GTP of the alpha subunit of G proteins, removal of agonist, and the action of phosphodiesterase on the second messenger (cAMP or cGMP) is what results in the downslope of the effect curve, the termination of the signal after agonist-receptor interaction.
Stroke is a leading cause of death worldwide and the most common cause of long-term disability amongst adults, more particularly in patients with diabetes mellitus and arterial hypertension. Increasing evidence suggests that disordered physiological variables following acute ischaemic stroke, especially hyperglycaemia, adversely affect outcomes.
Post-stroke hyperglycaemia is common (up to 50% of patients) and may be rather prolonged, regardless of diabetes status. A substantial body of evidence has demonstrated that hyperglycaemia has a deleterious effect upon clinical and morphological stroke outcomes. Therefore, hyperglycaemia represents an attractive physiological target for acute stroke therapies.
However, whether intensive glycaemic manipulation positively influences the fate of ischaemic tissue remains unknown. One major adverse event of management of hyperglycaemia with insulin (either glucose-potassium-insulin infusions or intensive insulin therapy) is the occurrence of hypoglycaemia, which can also induce cerebral damage.
Doctors all over the world have debated whether intensive glucose management, which requires the use of IV insulin to bring blood sugar levels down to 80-130 mg/dL, or standard glucose control using insulin shots, which aims to get glucose below 180 mg/dL, lead to better outcomes after stroke.
A period of hyperglycemia is common, with elevated blood glucose in the periinfarct period consistently linked with poor outcome in patients with and without diabetes. The mechanisms that underlie this deleterious effect of dysglycemia on ischemic neuronal tissue remain to be established, although in vitro research, functional imaging, and animal work have provided clues.
While prompt correction of hyperglycemia can be achieved, trials of acute insulin administration in stroke and other critical care populations have been equivocal. Diabetes mellitus and hyperglycemia per se are associated with poor cerebrovascular health, both in terms of stroke risk and outcome thereafter.
Interventions to control blood sugar are available but evidence of cerebrovascular efficacy are lacking. In diabetes, glycemic control should be part of a global approach to vascular risk while in acute stroke, theoretical data suggest intervention to lower markedly elevated blood glucose may be of benefit, especially if thrombolysis is administered.
Both hypoglycaemia and hyperglycaemia may lead to further brain injury and clinical deterioration; that is the reason these conditions should be avoided after stroke. Yet, when correcting hyperglycaemia, great care should be taken not to switch the patient into hypoglycaemia, and subsequently aggressive insulin administration treatment should be avoided.
Early identification and prompt management of hyperglycaemia, especially in acute ischaemic stroke, is recommended. Although the appropriate level of blood glucose during acute stroke is still debated, a reasonable approach is to keep the patient in a mildly hyperglycaemic state, rather than risking hypoglycaemia, using continuous glucose monitoring.
The primary results from the Stroke Hyperglycemia Insulin Network Effort (SHINE) study, a large, multisite clinical study showed that intensive glucose management did not improve functional outcomes at 90 days after stroke compared to standard glucose therapy. In addition, intense glucose therapy increased the risk of very low blood glucose (hypoglycemia) and required a higher level of care such as increased supervision from nursing staff, compared to standard treatment.
Today’s lesson 3 explains how extracellular signals are transduced (transmitted) into the cell through receptors to produce an agonist-driven event (effect). This lesson focused on signal transduction from agonist through G proteins (GTPases), and eventually to the effectors of the signal transduction process. Agonists such as small molecules like neurotransmitters, hormones, nitric oxide were discussed however later lectures will discuss more in detail the large growth factor signalings which occur through receptor tyrosine kinases and the Ras family of G proteins as well as mechanosignaling through Rho and Rac family of G proteins.
Transducers: The Heterotrimeric G Proteins (GTPases)
An excellent review of heterotrimeric G Proteins found in the brain is given by
Cyclic AMP is an important second messenger. It forms, as shown, when the membrane enzyme adenylyl cyclase is activated (as indicated, by the alpha subunit of a G protein).
The cyclic AMP then goes on the activate specific proteins. Some ion channels, for example, are gated by cyclic AMP. But an especially important protein activated by cyclic AMP is protein kinase A, which goes on the phosphorylate certain cellular proteins. The scheme below shows how cyclic AMP activates protein kinase A.
Updated 7/15/2019
Additional New Studies on Regulation of the Beta 2 Adrenergic Receptor
We had discussed regulation of the G protein coupled beta 2 adrenergic receptor by the B-AR receptor kinase (BARK)/B arrestin system which uncouples and desensitizes the receptor from its G protein system. In an article by Xiangyu Liu in Science in 2019, the authors describe another type of allosteric modulation (this time a POSITIVE allosteric modulation) in the intracellular loop 2. See below:
Mechanism of β2AR regulation by an intracellular positive allosteric modulator
Xiangyu Liu1,*, Ali Masoudi2,*, Alem W. Kahsai2,*, Li-Yin Huang2, Biswaranjan Pani2, Dean P. Staus2, Paul J. Shim2, Kunio Hirata3,4, Rishabh K. Simhal2, Allison M. Schwalb2, Paula K. Rambarat2, Seungkirl Ahn2, Robert J. Lefkowitz2,5,6,†, Brian Kobilka1
Positive reinforcement in a GPCR
Many drug discovery efforts focus on G protein–coupled receptors (GPCRs), a class of receptors that regulate many physiological processes. An exemplar is the β2-adrenergic receptor (β2AR), which is targeted by both blockers and agonists to treat cardiovascular and respiratory diseases. Most GPCR drugs target the primary (orthosteric) ligand binding site, but binding at allosteric sites can modulate activation. Because such allosteric sites are less conserved, they could possibly be targeted more specifically. Liu et al. report the crystal structure of β2AR bound to both an orthosteric agonist and a positive allosteric modulator that increases receptor activity. The structure suggests why the modulator compound is selective for β2AR over the closely related β1AR. Furthermore, the structure reveals that the modulator acts by enhancing orthosteric agonist binding and stabilizing the active conformation of the receptor.
Abstract
Drugs targeting the orthosteric, primary binding site of G protein–coupled receptors are the most common therapeutics. Allosteric binding sites, elsewhere on the receptors, are less well-defined, and so less exploited clinically. We report the crystal structure of the prototypic β2-adrenergic receptor in complex with an orthosteric agonist and compound-6FA, a positive allosteric modulator of this receptor. It binds on the receptor’s inner surface in a pocket created by intracellular loop 2 and transmembrane segments 3 and 4, stabilizing the loop in an α-helical conformation required to engage the G protein. Structural comparison explains the selectivity of the compound for β2– over the β1-adrenergic receptor. Diversity in location, mechanism, and selectivity of allosteric ligands provides potential to expand the range of receptor drugs.
Recent structures of GPCRs bound to allosteric modulators have revealed that receptor surfaces are decorated with diverse cavities and crevices that may serve as allosteric modulatory sites (1). This substantiates the notion that GPCRs are structurally plastic and can be modulated by a variety of allosteric ligands through distinct mechanisms (2-7). Most of these structures have been solved with negative allosteric modulators (NAMs), which stabilize receptors in their inactive states (1). To date, only a single structure of an active GPCR bound to a small-molecule positive allosteric modulator (PAM) has been reported, namely, the M2 muscarinic acetylcholine receptor with LY2119620 (8). Thus, mechanisms of PAMs and their potential binding sites remain largely unexplored.
Fig 1. Structure of the active state T4L-B2AR in complex with the orthosteric agonist BI-167107, nanobody 689, and compound 6FA. (A) The chemical structure of compound-6FA (Cmpd-6FA). (B) Isoproterenol (ISO) competition binding with 125I-cyanopindolol (CYP) to the β2AR reconstituted in nanodisks in the presence of vehicle (0.32% dimethylsulfoxide; DMSO), Cmpd-6, or Cmpd-6FA at 32 μM. Values were normalized to percentages of the maximal 125I-CYP binding level obtained from a one-site competition binding–log IC50 (median inhibitory concentration) curve fit. Binding curves were generated by GraphPad Prism. Points on curves represent mean ± SEM obtained from five independent experiments performed in duplicate. (C) Analysis of Cmpd-6FA interaction with the BI-167107–bound β2AR by ITC. Representative thermogram (inset) and binding isotherm, of three independent experiments, with the best titration curve fit are shown. Summary of thermodynamic parameters obtained by ITC: binding affinity (KD = 1.2 ± 0.1 μM), stoichiometry (N = 0.9 ± 0.1 sites), enthalpy (ΔH = 5.0 ± 1.2 kcal mol−1), and entropy (ΔS =13 ± 2.0 cal mol−1 deg−1). (D) Side view of T4L-β2AR bound to the orthosteric agonist BI-167107, nanobody 6B9 (Nb6B9), and Cmpd-6FA. The gray box indicates the membrane layer as defined by the OPM database. (E) Close-up view of Cmpd-6FA binding site. Covering Cmpd-6FA is 2Fo– Fc electron density contoured at 1.0 σ (green mesh).From Science 28 Jun 2019:
Vol. 364, Issue 6447, pp. 1283-1287
Fig 3. Fig. 3Mechanism of allosteric activation of the β2AR by Cmpd-6FA.
(A) Superposition of the inactive β2AR bound to the antagonist carazolol (PDB code: 2RH1) and the active β2AR bound to the agonist BI-167107, Cmpd-6FA, and Nb6B9. Close-up view of the Cmpd-6FA binding site is shown. The residues of the inactive (yellow) and active (blue) β2AR are depicted, and the hydrogen bond formed between Asp1303.49and Tyr141ICL2 in the active state is indicated by a black dashed line. (B) Topography of Cmpd-6FA binding surface on the active β2AR (left, blue) and the corresponding surface of the inactive β2AR (right, yellow) with Cmpd-6FA (orange sticks) docked on top. Molecular surfaces are of only those residues involved in interaction with Cmpd-6FA. Steric clash between Cmpd-6FA and the surface of inactive β2AR is represented by a purple asterisk. (C) Overlay of the β2AR bound to BI-167107, Nb6B9, and Cmpd-6FA with the β2AR–Gscomplex (PDB code: 3SN6). The inset shows the position of Phe139ICL2 relative to the α subunit of Gs. (D) Superposition of the active β2AR bound to the agonist BI-167107, Nb6B9, and Cmpd-6FA (blue) with the inactive β2AR bound to carazolol (yellow) (PDB code: 2RH1) as viewed from the cytoplasm. For clarity, Nb6B9 and the orthosteric ligands are omitted. The arrows indicate shifts in the intracellular ends of the TM helices 3, 5, and 6 upon activation and their relative distances.
Allosteric sites may not face the same evolutionary pressure as do orthosteric sites, and thus are more divergent across subtypes within a receptor family (24–26). Therefore, allosteric sites may provide a greater source of specificity for targeting GPCRs.
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Additional information on Nitric Oxide as a Cellular Signal
Nitric oxide is actually a free radical and can react with other free radicals, resulting in a very short half life (only a few seconds) and so in the body is produced locally to its site of action (i.e. in endothelial cells surrounding the vascular smooth muscle, in nerve cells). In the late 1970s, Dr. Robert Furchgott observed that acetylcholine released a substance that produced vascular relaxation, but only when the endothelium was intact. This observation opened this field of research and eventually led to his receiving a Nobel prize. Initially, Furchgott called this substance endothelium-derived relaxing factor (EDRF), but by the mid-1980s he and others identified this substance as being NO.
Nitric oxide is implicated in many pathologic processes as well. Nitric oxide post translational modifications have been attributed to nitric oxide’s role in pathology however, although the general mechanism by which nitric oxide exerts its physiological effects is by stimulation of soluble guanylate cyclase to produce cGMP, these post translational modifications can act as a cellular signal as well. For more information of NO pathologic effects and how NO induced post translational modifications can act as a cellular signal see the following:
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