Healthcare analytics, AI solutions for biological big data, providing an AI platform for the biotech, life sciences, medical and pharmaceutical industries, as well as for related technological approaches, i.e., curation and text analysis with machine learning and other activities related to AI applications to these industries.
A highly effective platforms for the ex utero culture of post-implantation mouse embryos have been developed in the present study by scientists of the Weizmann Institute of Science in Israel. The study was published in the journal Nature. They have grown more than 1,000 embryos in this way. This study enables the appropriate development of embryos from before gastrulation (embryonic day (E) 5.5) until the hindlimb formation stage (E11). Late gastrulating embryos (E7.5) are grown in three-dimensional rotating bottles, whereas extended culture from pre-gastrulation stages (E5.5 or E6.5) requires a combination of static and rotating bottle culture platforms.
At Day 11 of development more than halfway through a mouse pregnancy the researchers compared them to those developing in the uteruses of living mice and were found to be identical. Histological, molecular and single-cell RNA sequencing analyses confirm that the ex utero cultured embryos recapitulate in utero development precisely. The mouse embryos looked perfectly normal. All their organs developed as expected, along with their limbs and circulatory and nervous systems. Their tiny hearts were beating at a normal 170 beats per minute. But, the lab-grown embryos becomes too large to survive without a blood supply. They had a placenta and a yolk sack, but the nutrient solution that fed them through diffusion was no longer sufficient. So, a suitable mechanism for blood supply is required to be developed.
Till date the only way to study the development of tissues and organs is to turn to species like worms, frogs and flies that do not need a uterus, or to remove embryos from the uteruses of experimental animals at varying times, providing glimpses of development more like in snapshots than in live videos. This research will help scientists understand how mammals develop and how gene mutations, nutrients and environmental conditions may affect the fetus. This will allow researchers to mechanistically interrogate post-implantation morphogenesis and artificial embryogenesis in mammals. In the future it may be possible to develop a human embryo from fertilization to birth entirely outside the uterus. But the work may one day raise profound questions about whether other animals, even humans, should or could be cultured outside a living womb.
What Is Gene Therapy? How Does It Save and Improve the Quality of Life?
What Is Gene Therapy?
Gene therapy is a new and exciting technique, defined as the use of genetic material to cure or alleviate disease. It is considered revolutionary, yet still in its infancy, with many new therapies currently undergoing clinical trials.
Gene therapy has the potential to transform the treatment for diseases, significantly changing how doctors manage and treat patients.
Two Types of Gene Therapy
There are two main types of gene therapy.
The first corrects a specific disease causing genetic mutation. These are targeted towards inherited genetic disorders such as hemophilia or Duchenne muscular dystrophy. The second gives new functions to cells allowing them to fight disease.
A good example of these therapies are chimeric antigen receptor T cell (CAR-T) therapies. Both Novartis’ Kymriah♦ and Gilead’s Yescarta♦ are examples of CAR-T therapies, that have demonstrated exceptional cancer remission rates where other forms of treatment have failed.
Cancer is the by far the largest category of disease with 65% of gene therapy clinical trials being investigated, followed by 11.1% for inherited monogenetic disease, 7% for infectious disease, and 6.9% for cardiovascular disease1.
How Does Genetic Material Get Delivered to Host Cell(s)?
Genetic material gets delivered to a host cell via a delivery system known as a vector. Vectors deliver genetic material via one of the two methods. By directly injecting genetic material into the patient (in vivo), and where selected cells collected from the patient, undergo modification outside (ex vivo) before introducing them back into the patient.
The most commonly used type of vector is a virus. While there are other methods of delivering genetic material into a cell, viruses have now been developed that demonstrate a good balance between efficacy and safety.
Commercially Successful Gene Therapies
Developing a commercially successful gene therapy is challenging. It requires balancing several different considerations. Having a clinical effective therapy is essential, but this alone is not sufficient to ensure product success. In addition to this, reimbursement, quality and regulatory considerations, and manufacturing also must be considered.
To date, a total 11 gene therapies have received marketing approval. However, behind this there is a strong clinical pipeline with >1000 clinical trials underway, and 92 drugs in Phase 32.
Furthermore, there has been significant investment with >$50B being invested in the area in the past 3 years3.
This investment, coupled with the accelerating understanding of disease at the genetic level, holds immense potential. Academic, commercial manufacturers, and industry suppliers are actively seeking new approaches that deliver these therapies as quick as possible to a waiting population.
Top Industrialization Challenges of Gene Therapy Manufacturing
Manufacturing and scale-up of industrialized processes to manufacture gene therapy products are accompanied by many challenges that must be overcome to succeed in the marketplace. Commercialization of gene therapies for patient use is time consuming and requires substantial financial investment and dedicated resources.
Despite the unique range of challenges associated with gene therapy development, the quest to bring these therapies to market is worthwhile because the therapeutic potential of the treatments is revolutionary and the commercial opportunity is considerable. The process to industrialization is complex, but the benefits of successful development of robust processes are huge. The industry is rapidly expanding and is implementing novel approaches to overcome existing challenges, using innovative methods for medicinal application and developing new drugs to treat rare diseases.
Manufacturing sufficient quantities of high quality product, is an area that requires substantial developmental effort. Challenges surrounding reimbursement for treatment, and the pressures associated with shorter time to approval, both increase burden placed on manufactures to rapidly develop suitable processes that are cost-effective. Cost of goods (COGs) need to be kept below critical threshold levels to drive sufficient profit margins, even though process development timelines are aggressive and short. There are a multitude of critical decisions and considerations to overcome.
This blog explores some of these fundamental manufacturing challenges in more detail.
Scalable Manufacturing Platform
Technologies used to manufacture gene therapy biologics are advancing at very rapid pace. Not having a platform that is suitable nor scalable is a significant challenge many manufacturers face. It is a necessity throughout clinical development stages to be able to optimize the manufacturing process. However, any change in the manufacturing process that increases product yield or enhances quality is accompanied by the risk of changing the product. It is therefore essential that close attention is paid to tracking variation throughout the development process at every stage.
A substantial amount of early stage development is still being performed using outdated, non-commercially viable platforms and transferring processes to new platforms is required. To achieve manufacturing platform advancement, the product needs to be very well characterized during development so that investigators can generate data sets which demonstrate comparability between products used in clinical studies and those generated with the final manufacturing process.
Cost of Goods
COGs associated with manufacturing any drug product impacts the overall price of the therapy and heavily influences the profit margin realized by gene therapy manufactures. High production cost is a challenge that affects profitability. This is reflected in the high costs associated with newly approved gene therapy drugs such as Yescarta♦, Kymriah♦ and Luxturna♦ which are currently priced in the 100 thousands dollar range per dose. The challenge becomes a critical concern when the product in development cannot be sold at a price high enough to achieve a commercially-viable profit margin. If acceptable margins cannot be reached, developers may choose to terminate production making the drug unavailable to patients. However, due to the remarkable value and life changing nature of the treatments the entire industry is committed to the pursuit of cost effective methods for manufacturing. There is a significant effort that has been mounted by all players to reach this end.
Currently, the main cost contributor to the overall COGs for gene therapy products is high quality clinical grade plasmid DNA containing the therapeutic gene of interest. This reagent is required for transient transfection of cells and it is imperative that the reagent is of high quality. It is an essential component of the process to assure an acceptable safety profile. Another example of an expensive gene therapy product is Zolgensma♦. This new drug was recently approved for the treatment of spinal muscular atrophy (SMA), which is a rare disease that causes severe muscle weakness for suffers. It affects their ability to breath, speak and move. Most babies born with a common form of SMA die by the time they reach two years of age. Currently there is no cure. Zolgensma represents the only treatment option now available to cure the 10,000 – 25,000 affected individuals in the US. However, the current challenge with this therapy is that it could costs $2.1 million per patient1.
Reimbursement
Market size is an important factor that can limit effective commercial return. If the market size is too small, profitability is limited due to the small number of doses required to treat the patient population. This decreases the profit margin realized by the drug developer and can lower motivation to commercialize the therapy. The most encouraging aspect of the gene therapy revolution is that the first round of gene therapy products has been developed for extremely rare diseases, with small patient populations indicating the commitment to treat previously untreatable diseases. Amazingly, these patients can be cured by a single drug application, however, this inherent property of the therapy can further limit commercial profitability. Patients are often not required to pay for these high-cost medicines themselves, and look to government programs and health care insurance providers to reimburse the manufacturer for treatments. Health insurance reimbursement plans for new products is challenging, particularly so for new category products like gene therapy. It is expected that the process of reimbursement will differ from country to country and it will also be guided by factors like economics, demographic data and politics. If the current cost of manufacturing stands then drugs such as Zolgensma could place a huge financial strain on health systems. In the US for example, it is surmised that treating common diseases such as hemophilia, which affects around 20,000 people in the US alone, could cause a financial crisis1. If we look to the future of modern medicine, commercialization of gene therapies will require not only significant advancement in manufacturing processes to reduce costs but also a practical reimbursement strategy that will allow for drug developers to continue to forge into the new frontiers of medicine.
♦Kymriah is a trademark of Novartis AG., Luxturna is a trademark of Spark Therapeutics, Inc., Yescarta is a trademark of Kite Pharma, Inc., Zolgensma is a trademark of AveXis Inc.
Gene Therapy could be a Boon to Alzheimer’s disease (AD): A first-in-human clinical trial proposed
Reporter: Dr. Premalata Pati, Ph.D., Postdoc
A recent research work performed by the Researchers at the University of California San Diego School of Medicine has shared their first-in-human Phase I clinical trial to assess the safety and viability of gene therapy to deliver a key protein into the brains of persons with Alzheimer’s Disease (AD) or Mild Cognitive Impairment (MCI), a condition that often precedes full-blown dementia.
Mark Tuszynski, M.D., Ph.D., Professor of Neuroscience and Director of the Translational Neuroscience Institute at UC San Diego and team predicted that Gene therapy could be a boon to potential treatments for the disorders like AD and MCI.
The study provides an insight into the genetic source of these mental diseases.
The roots of mental disorders have remained an enigma for so many years. Alzheimer’s disease (AD) is an irreversible, progressive brain disorder that slowly destroys memory and thinking skills and, eventually, the ability to carry out the simplest tasks. AD is a neurodegenerative condition. A buildup of plaques and tangles in the brain, along with cell death, causes memory loss and cognitive decline. In most people with the disease, those with the late-onset type – symptoms first appear in their mid-60s. Alzheimer’s disease is the mostly appearing type of dementia in patients.
Despite decades of effort and billions of dollars of research investment, there are just mere two symptomatic treatments for AD. There is no cure or approved way to slow or stop the progression of the neurological disorder that afflicts more than 5 million Americans and is the sixth leading cause of death in the United States.
Prof. Tuszynski said gene therapy has been tested on multiple diseases and conditions, represents a different approach to a disease that requires new ways of thinking about the disease and new attempts at treatments.
The research team found that delivering the BDNF to the part of the brain that is affected earliest in Alzheimer’s disease; the entorhinal cortex and hippocampus – was able to protect from ongoing cell degeneration by reversing the loss of connections. “These trials were observed in aged rats, amyloid mice, and aged monkeys.”
The protein, calledBrain-Derived Neurotrophic Factor or BDNF, a family of growth factors found in the Brain and Central Nervous System that support the survival of existing neurons and promote growth and differentiation of new neurons and synapses. BDNF is especially important in brain regions susceptible to degeneration in AD. It is normally produced throughout life in the entorhinal cortex, an important memory center in the brain and one of the first places where the effects of AD typically appear in the form of short-term memory loss. Persons with AD have diminished levels of BDNF.
However, BDNF is a large molecule and cannot pass through the Blood-Brain Barrier. As a solution, researchers will use gene therapy in which a harmless Adeno-Associated Virus (AAV2) is modified to carry the BDNF gene and injected directly into targeted regions of the brain, where researchers hope it will prompt the production of therapeutic BDNF in nearby cells.
Precautions were taken precisely in injecting the patient to avoid exposure to surrounding degenerating neurons since freely circulating BDNF can cause adverse effects, such as seizures or epileptic conditions.
The recent research and study speculate a safe and feasible assessment of the AAV2-BDNF pathway in humans. A previous gene therapy trial from 2001 to 2012 using AAV2 and a different protein called Nerve Growth Factor (NGF) was carried out by Prof. Tuszynski and team where they observed immense growth, axonal sprouting, and activation of functional markers in the brains of participants.
He also shared that “The BDNF gene therapy trial in AD represents an advancement over the earlier NGF trial, BDNF is a more potent growth factor than NGF for neural circuits that degenerate in AD. Besides, new methods for delivering BDNF will more effectively deliver and distribute it into the entorhinal cortex and hippocampus.”
The research team hopes that the three-year-long trial will recruit 12 participants with either diagnosed AD or MCI to receive AAV2-BDNF treatment, with another 12 persons serving as comparative controls over that period.
The researchers have plans to build on recent successes of gene therapy in other diseases, including a breakthrough success in the treatment of congenital weakness in infants(spinal muscular atrophy) and blindness (Leber Hereditary Optic Neuropathy, a form of retinitis pigmentosa).”
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.
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
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.
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
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
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
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
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
Cell therapy vs transplant therapy no immunosuppression
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?
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?
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.
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.
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
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.
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?
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
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.
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
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.
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
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
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
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
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
Cell therapy vs transplant therapy no immunosuppression
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?
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?
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.
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.
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
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.
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?
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
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.
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?
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.
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?
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.
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
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.
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
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
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
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
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
Cell therapy vs transplant therapy no immunosuppression
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?
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?
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.
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.
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
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.
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?
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 oxygenation in location lymphatic and vascularization control 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.
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?
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?
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.
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.
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.
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?
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.
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?
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?
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.
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.
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?
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?
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.
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.
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.
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?
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.
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?
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?
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.
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
Inhibitory CD161 receptor recognized as a potential immunotherapy target in glioma-infiltrating T cells by single-cell analysis
Reporter: Dr. Premalata Pati, Ph.D., Postdoc
Brain tumors, especially the diffused Gliomas are of the most devastating forms of cancer and have so-far been resistant to immunotherapy. It is comprehended that T cells can penetrate the glioma cells, but it still remains unknown why infiltrating cells miscarry to mount a resistant reaction or stop the tumor development.
Gliomas are brain tumors that begin from neuroglial begetter cells. The conventional therapeutic methods including, surgery, chemotherapy, and radiotherapy, have accomplished restricted changes inside glioma patients. Immunotherapy, a compliance in cancer treatment, has introduced a promising strategy with the capacity to penetrate the blood-brain barrier. This has been recognized since the spearheading revelation of lymphatics within the central nervous system. Glioma is not generally carcinogenic. As observed in a number of cases, the tumor cells viably reproduce and assault the adjoining tissues, by and large, gliomas are malignant in nature and tend to metastasize. There are four grades in glioma, and each grade has distinctive cell features and different treatment strategies. Glioblastoma is a grade IV glioma, which is the crucial aggravated form. This infers that all glioblastomas are gliomas, however, not all gliomas are glioblastomas.
Decades of investigations on infiltrating gliomas still take off vital questions with respect to the etiology, cellular lineage, and function of various cell types inside glial malignancies. In spite of the available treatment options such as surgical resection, radiotherapy, and chemotherapy, the average survival rate for high-grade glioma patients remains 1–3 years (1).
A recent in vitro study performed by the researchers of Dana-Farber Cancer Institute, Massachusetts General Hospital, and the Broad Institute of MIT and Harvard, USA, has recognized that CD161 is identified as a potential new target for immunotherapy of malignant brain tumors. The scientific team depicted their work in the Cell Journal, in a paper entitled, “Inhibitory CD161 receptor recognized in glioma-infiltrating T cells by single-cell analysis.” on 15th February 2021.
To further expand their research and findings, Dr. Kai Wucherpfennig, MD, PhD, Chief of the Center for Cancer Immunotherapy, at Dana-Farber stated that their research is additionally important in a number of other major human cancer types such as
melanoma,
lung,
colon, and
liver cancer.
Dr. Wucherpfennig has praised the other authors of the report Mario Suva, MD, PhD, of Massachusetts Common Clinic; Aviv Regev, PhD, of the Klarman Cell Observatory at Broad Institute of MIT and Harvard, and David Reardon, MD, clinical executive of the Center for Neuro-Oncology at Dana-Farber.
Hence, this new study elaborates the effectiveness of the potential effectors of anti-tumor immunity in subsets of T cells that co-express cytotoxic programs and several natural killer (NK) cell genes.
The Study-
IMAGE SOURCE: Experimental Strategy (Mathewson et al., 2021)
The group utilized single-cell RNA sequencing (RNA-seq) to mull over gene expression and the clonal picture of tumor-infiltrating T cells. It involved the participation of 31 patients suffering from diffused gliomas and glioblastoma. Their work illustrated that the ligand molecule CLEC2D activates CD161, which is an immune cell surface receptor that restrains the development of cancer combating activity of immune T cells and tumor cells in the brain. The study reveals that the activation of CD161 weakens the T cell response against tumor cells.
Based on the study, the facts suggest that the analysis of clonally expanded tumor-infiltrating T cells further identifies the NK gene KLRB1 that codes for CD161 as a candidate inhibitory receptor. This was followed by the use of
CRISPR/Cas9 gene-editing technology to inactivate the KLRB1 gene in T cells and showed that CD161 inhibits the tumor cell-killing function of T cells. Accordingly,
genetic inactivation of KLRB1 or
antibody-mediated CD161 blockade
enhances T cell-mediated killing of glioma cells in vitro and their anti-tumor function in vivo. KLRB1 and its associated transcriptional program are also expressed by substantial T cell populations in other forms of human cancers. The work provides an atlas of T cells in gliomas and highlights CD161 and other NK cell receptors as immune checkpoint targets.
Further, it has been identified that many cancer patients are being treated with immunotherapy drugs that disable their “immune checkpoints” and their molecular brakes are exploited by the cancer cells to suppress the body’s defensive response induced by T cells against tumors. Disabling these checkpoints lead the immune system to attack the cancer cells. One of the most frequently targeted checkpoints is PD-1. However, recent trials of drugs that target PD-1 in glioblastomas have failed to benefit the patients.
In the current study, the researchers found that fewer T cells from gliomas contained PD-1 than CD161. As a result, they said, “CD161 may represent an attractive target, as it is a cell surface molecule expressed by both CD8 and CD4 T cell subsets [the two types of T cells engaged in response against tumor cells] and a larger fraction of T cells express CD161 than the PD-1 protein.”
However, potential side effects of antibody-mediated blockade of the CLEC2D-CD161 pathway remain unknown and will need to be examined in a non-human primate model. The group hopes to use this finding in their future work by
utilizing their outline by expression of KLRB1 gene in tumor-infiltrating T cells in diffuse gliomas to make a remarkable contribution in therapeutics related to immunosuppression in brain tumors along with four other common human cancers ( Viz. melanoma, non-small cell lung cancer (NSCLC), hepatocellular carcinoma, and colorectal cancer) and how this may be manipulated for prevalent survival of the patients.
References
(1) Anders I. Persson, QiWen Fan, Joanna J. Phillips, William A. Weiss, 39 – Glioma, Editor(s): Sid Gilman, Neurobiology of Disease, Academic Press, 2007, Pages 433-444, ISBN 9780120885923, https://doi.org/10.1016/B978-012088592-3/50041-4.
4.1.3 Single-cell Genomics: Directions in Computational and Systems Biology – Contributions of Prof. Aviv Regev @Broad Institute of MIT and Harvard, Cochair, the Human Cell Atlas Organizing Committee with Sarah Teichmann of the Wellcome Trust Sanger Institute
4.1.7 Norwich Single-Cell Symposium 2019, Earlham Institute, single-cell genomics technologies and their application in microbial, plant, animal and human health and disease, October 16-17, 2019, 10AM-5PM
Positron Emission Tomography (PET) and Near-Infrared Fluorescence Imaging: Noninvasive Imaging of Cancer Stem Cells (CSCs) monitoring of AC133+ glioblastoma in subcutaneous and intracerebral xenograft tumors
Cancer treatment using CRISPR-based Genome Editing System
Reporter: Irina Robu, PhD
CRISPR, stands for “clusters of regularly interspaced short palindromic repeats” is one of the biggest accomplishments in science of this decade and it is the simplest tool for altering DNA sequences and modifying gene functions. The technology is adapted form the natural defense mechanism of bacteria. Bacteria uses CRISPR-derived RNA and different Cas proteins to foil attacks by viruses and foreign bodies.
Scientists in the laboratory of Prof. Dan Peer, VP for R&D and Head of the Laboratory of Precision Nanomedicine at the Shmunis School of Biomedicine and Cancer Research at TAU have shown that CRISPR/Cas9 system is efficient in treating metastatic cancer. They developed a novel lipid nanoparticle-based delivery system that targets cancer cells and ends them by genetic manipulation, called CRISPR-LNPs, which were published in published in November 2020 in Science Advances.
Professor Peer and his team of scientists chose two of the deadliest cancers: glioblastoma and metastatic ovarian cancer to prove that CRISPR genome editing system can be used to treat cancer effectively in a living animal. Since, glioblastoma is the most aggressive type of brain cancer with a life expectancy of 15 months after diagnosis, the researchers showed that the single treatment with CRISPR-LNPs doubled the average life expectancy of mice with glioblastoma tumors. At the same time, ovarian cancer is the most lethal cancer of female reproductive system and many patients are usually diagnosed at the advance stage of the disease. Treatment with CRISPR-LNPs in a metastatic ovarian cancer mice model increased their overall survival rate by 80%.
Despite CRISPR genome editing technology being capable of identifying and altering any genetic segment, clinical implementation is still in its infancy because the inability to accurately deliver the CRISPR to the target cells. In order to solve the issue, Professor Peer developed a delivery system that targets the DNA responsible for the cancer cells.
By demonstrating that the technology can treat two aggressive cancers, researchers open the technology to numerous new possibilities for treating other types of cancer. They intend to go on to experiments with blood cancers which are very interesting genetically.
Genetic scissors: a tool for rewriting the code of life
Emmanuelle Charpentier and Jennifer A. Doudna have discovered one of gene technology’s sharpest tools: the CRISPR/Cas9 genetic scissors. Using these, researchers can change the DNA of animals, plants and microorganisms with extremely high precision. This technology has had a revolutionary impact on the life sciences, is contributing to new cancer therapies and may make the dream of curing inherited diseases come true.
Researchers need to modify genes in cells if they are to find out about life’s inner workings. This used to be time-consuming, difficult and sometimes impossible work. Using the CRISPR/Cas9 genetic scissors, it is now possible to change the code of life over the course of a few weeks.
“There is enormous power in this genetic tool, which affects us all. It has not only revolutionised basic science, but also resulted in innovative crops and will lead to ground-breaking new medical treatments,” says Claes Gustafsson, chair of the Nobel Committee for Chemistry.
As so often in science, the discovery of these genetic scissors was unexpected. During Emmanuelle Charpentier’s studies of Streptococcus pyogenes, one of the bacteria that cause the most harm to humanity, she discovered a previously unknown molecule, tracrRNA. Her work showed that tracrRNA is part of bacteria’s ancient immune system, CRISPR/Cas, that disarms viruses by cleaving their DNA.
Charpentier published her discovery in 2011. The same year, she initiated a collaboration with Jennifer Doudna, an experienced biochemist with vast knowledge of RNA. Together, they succeeded in recreating the bacteria’s genetic scissors in a test tube and simplifying the scissors’ molecular components so they were easier to use.
In an epoch-making experiment, they then reprogrammed the genetic scissors. In their natural form, the scissors recognise DNA from viruses, but Charpentier and Doudna proved that they could be controlled so that they can cut any DNA molecule at a predetermined site. Where the DNA is cut it is then easy to rewrite the code of life.
Since Charpentier and Doudna discovered the CRISPR/Cas9 genetic scissors in 2012 their use has exploded. This tool has contributed to many important discoveries in basic research, and plant researchers have been able to develop crops that withstand mould, pests and drought. In medicine, clinical trials of new cancer therapies are underway, and the dream of being able to cure inherited diseases is about to come true. These genetic scissors have taken the life sciences into a new epoch and, in many ways, are bringing the greatest benefit to humankind.
Emmanuelle Charpentier, born 1968 in Juvisy-sur-Orge, France. Ph.D. 1995 from Institut Pasteur, Paris, France. Director of the Max Planck Unit for the Science of Pathogens, Berlin, Germany.
Jennifer A. Doudna, born 1964 in Washington, D.C, USA. Ph.D. 1989 from Harvard Medical School, Boston, USA. Professor at the University of California, Berkeley, USA and Investigator, Howard Hughes Medical Institute.
Other Articles on the Nobel Prize in this Open Access Journal Include:
there have been many instances of off-target effects where genes, other than the selected target, are edited out. This ‘off-target’ issue has hampered much of the utility of CRISPR in gene-therapy and CART therapy
However, an article in Science by Jon Cohen explains a Nature paper’s finding of a new tool in the CRISPR arsenal called prime editing, meant to increase CRISPR specificity and precision editing capabilities.
Primeediting promises to be a cut above CRISPR Jon Cohen CRISPR, an extraordinarily powerful genome-editing tool invented in 2012, can still be clumsy. … Primeediting steers around shortcomings of both techniques by heavily modifying the Cas9 protein and the guide RNA. … ” Primeediting “well may become the way that disease-causing mutations are repaired,” he says.
The effort, led by Drs. David Liu and Andrew Anzalone at the Broad Institute (Cambridge, MA), relies on the modification of the Cas9 protein and guide RNA, so that there is only a nick in a single strand of the double helix. The canonical Cas9 cuts both strands of DNA, and so relies on an efficient gap repair activity of the cell. The second part, a new type of guide RNA called a pegRNA, contains an RNA template for a new DNA sequence to be added at the target location. This pegRNA-directed synthesis of the new template requires the attachment of a reverse transcriptase enzymes to the Cas9. So far Liu and his colleagues have tested the technology on over 175 human and rodent cell lines with great success. In addition, they had also corrected mutations which cause Tay Sachs disease, which previous CRISPR systems could not do. Liu claims that this technology could correct over 89% of pathogenic variants in human diseases.
A company Prime Medicine has been formed out of this effort.
As was announced, prime editing for human therapeutics will be jointly developed by both Prime Medicine and Beam Therapeutics, each focusing on different types of edits and distinct disease targets, which will help avoid redundancy and allow us to cover more disease territory overall. The companies will also share knowledge in prime editing as well as in accompanying technologies, such as delivery and manufacturing.
Reader of StatNews.: Can you please compare the pros and cons of prime editing versus base editing?
The first difference between base editing and prime editing is that base editing has been widely used for the past 3 1/2 years in organisms ranging from bacteria to plants to mice to primates. Addgene tells me that the DNA blueprints for base editors from our laboratory have been distributed more than 7,500 times to more than 1,000 researchers around the world, and more than 100 research papers from many different laboratories have been published using base editors to achieve desired gene edits for a wide variety of applications. While we are very excited about prime editing, it’s brand-new and there has only been one paper published thus far. So there’s much to do before we can know if prime editing will prove to be as general and robust as base editing has proven to be.
We directly compared prime editors and base editors in our study, and found that current base editors can offer higher editing efficiency and fewer indel byproducts than prime editors, while prime editors offer more targeting flexibility and greater editing precision. So when the desired edit is a transition point mutation (C to T, T to C, A to G, or G to A), and the target base is well-positioned for base editing (that is, a PAM sequence exists approximately 15 bases from the target site), then base editing can result in higher editing efficiencies and fewer byproducts. When the target base is not well-positioned for base editing, or when other “bystander” C or A bases are nearby that must not be edited, then prime editing offers major advantages since it does not require a precisely positioned PAM sequence and is a true “search-and-replace” editing capability, with no possibility of unwanted bystander editing at neighboring bases.
Of course, for classes of mutations other than the four types of point mutations that base editors can make, such as insertions, deletions, and the eight other kinds of point mutations, to our knowledge prime editing is currently the only approach that can make these mutations in human cells without requiring double-stranded DNA cuts or separate DNA templates.
Nucleases (such as the zinc-finger nucleases, TALE nucleases, and the original CRISPR-Cas9), base editors, and prime editors each have complementary strengths and weaknesses, just as scissors, pencils, and word processors each have unique and useful roles. All three classes of editing agents already have or will have roles in basic research and in applications such as human therapeutics and agriculture.
Most genetic variants that contribute to disease1 are challenging to correct efficiently and without excess byproducts2,3,4,5. Here we describe prime editing, a versatile and precise genome editing method that directly writes new genetic information into a specified DNA site using a catalytically impaired Cas9 endonuclease fused to an engineered reverse transcriptase, programmed with a prime editing guide RNA (pegRNA) that both specifies the target site and encodes the desired edit. We performed more than 175 edits in human cells, including targeted insertions, deletions, and all 12 types of point mutation, without requiring double-strand breaks or donor DNA templates. We used prime editing in human cells to correct, efficiently and with few byproducts, the primary genetic causes of sickle cell disease (requiring a transversion in HBB) and Tay–Sachs disease (requiring a deletion in HEXA); to install a protective transversion in PRNP; and to insert various tags and epitopes precisely into target loci. Four human cell lines and primary post-mitotic mouse cortical neurons support prime editing with varying efficiencies. Prime editing shows higher or similar efficiency and fewer byproducts than homology-directed repair, has complementary strengths and weaknesses compared to base editing, and induces much lower off-target editing than Cas9 nuclease at known Cas9 off-target sites. Prime editing substantially expands the scope and capabilities of genome editing, and in principle could correct up to 89% of known genetic variants associated with human diseases.
From Anzolone et al. Nature 2019 Figure 1.
Prime editing strategy
Cas9 targets DNA using a guide RNA containing a spacer sequence that hybridizes to the target DNA site. We envisioned the generation of guide RNAs that both specify the DNA target and contain new genetic information that replaces target DNA nucleotides. To transfer information from these engineered guide RNAs to target DNA, we proposed that genomic DNA, nicked at the target site to expose a 3′-hydroxyl group, could be used to prime the reverse transcription of an edit-encoding extension on the engineered guide RNA (the pegRNA) directly into the target site (Fig. 1b, c, Supplementary Discussion).
These initial steps result in a branched intermediate with two redundant single-stranded DNA flaps: a 5′ flap that contains the unedited DNA sequence and a 3′ flap that contains the edited sequence copied from the pegRNA (Fig. 1c). Although hybridization of the perfectly complementary 5′ flap to the unedited strand is likely to be thermodynamically favoured, 5′ flaps are the preferred substrate for structure-specific endonucleases such as FEN122, which excises 5′ flaps generated during lagging-strand DNA synthesis and long-patch base excision repair. The redundant unedited DNA may also be removed by 5′ exonucleases such as EXO123.
The authors reasoned that preferential 5′ flap excision and 3′ flap ligation could drive the incorporation of the edited DNA strand, creating heteroduplex DNA containing one edited strand and one unedited strand (Fig. 1c).
DNA repair to resolve the heteroduplex by copying the information in the edited strand to the complementary strand would permanently install the edit (Fig. 1c).
They had hypothesized that nicking the non-edited DNA strand might bias DNA repair to preferentially replace the non-edited strand.
Results
The authors evaluated the eukaryotic cell DNA repair outcomes of 3′ flaps produced by pegRNA-programmed reverse transcription in vitro, and performed in vitro prime editing on reporter plasmids, then transformed the reaction products into yeast cells (Extended Data Fig. 2).
Reporter plasmids encoding EGFP and mCherry separated by a linker containing an in-frame stop codon, +1 frameshift, or −1 frameshift were constructed and when plasmids were edited in vitro with Cas9 nickase, RT, and 3′-extended pegRNAs encoding a transversion that corrects the premature stop codon, 37% of yeast transformants expressed both GFP and mCherry (Fig. 1f, Extended Data Fig. 2).
They fused a variant of M—MLV-RT (reverse transcriptase) to Cas9 with an extended linker and this M-MLV RT fused to the C terminus of Cas9(H840A) nickase was designated as PE1. This strategy allowed the authors to generate a cell line containing all the required components of the primer editing system. They constructed 19 variants of PE1 containing a variety of RT mutations to evaluate their editing efficiency in human cells
Generated a pentamutant RT incorporated into PE1 (Cas9(H840A)–M-MLV RT(D200N/L603W/T330P/T306K/W313F)) is hereafter referred to as prime editor 2 (PE2). These were more thermostable versions of RT with higher efficiency.
Optimized the guide (pegRNA) using a series of permutations and recommend starting with about 10–16 nt and testing shorter and longer RT templates during pegRNA optimization.
In the previous attempts (PE1 and PE2 systems), mismatch repair resolves the heteroduplex to give either edited or non-edited products. So they next developed an optimal editing system (PE3) to produce optimal nickase activity and found nicks positioned 3′ of the edit about 40–90 bp from the pegRNA-induced nick generally increased editing efficiency (averaging 41%) without excess indel formation (6.8% average indels for the sgRNA with the highest editing efficiency) (Fig. 3b).
The cell line used to finalize and validate the system was predominantly HEK293T immortalized cell line
Together, their findings establish that PE3 systems improve editing efficiencies about threefold compared with PE2, albeit with a higher range of indels than PE2. When it is possible to nick the non-edited strand with an sgRNA that requires editing before nicking, the PE3b system offers PE3-like editing levels while greatly reducing indel formation.
Off Target Effects: Strikingly, PE3 or PE2 with the same 16 pegRNAs containing these four target spacers resulted in detectable off-target editing at only 3 out of 16 off-target sites, with only 1 of 16 showing an off-target editing efficiency of 1% or more (Extended Data Fig. 6h). Average off-target prime editing for pegRNAs targeting HEK3, HEK4, EMX1, and FANCFat the top four known Cas9 off-target sites for each protospacer was <0.1%, <2.2 ± 5.2%, <0.1%, and <0.13 ± 0.11%, respectively (Extended Data Fig. 6h).
The PE3 system was very efficient at editing the most common mutation that causes Tay-Sachs disease, a 4-bp insertion in HEXA(HEXA1278+TATC).
References
Landrum, M. J. et al. ClinVar: public archive of interpretations of clinically relevant variants. Nucleic Acids Res. 44, D862–D868 (2016).
Jinek, M. et al. A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science337, 816–821 (2012).
Kosicki, M., Tomberg, K. & Bradley, A. Repair of double-strand breaks induced by CRISPR–Cas9 leads to large deletions and complex rearrangements. Biotechnol. 36, 765–771 (2018).
First of all, a big thank you to everyone who attended yesterday’s webinar on a new approach for exploring the dark genome. If you missed it, you can still watch it ‘on demand’ here.
In the last week, we’ve also launched two more webinar series. Both are free to attend and available live or on-demand:
Single Cell Online: A series of 4 webinars in July, starting on the 9th, focusing on unleashing the full power of single cell technologies. The series includes contributors from Novartis, Merck, Sanofi, Roche, the University of Gothenburg, MGI and Partek. Find out more and register here.
Driving FAIR in BioPharma: A series of 3 webinars in July and August, starting on the 21st July, exploring various use cases of FAIR data implementation to enable the potential of AI and ML in R&D. The series features contributors from AstraZeneca, Roche, Novartis, University of Oxford, ONTOFORCE, FDA, Eurofins and CDD. Click here to find out more and register.
Finally, this week on the website we have some fantastic content for you, including articles on the use of single cell analysis in COVID-19 research and a machine learning model that can predict base-editing outcomes. There’s also the latest DNA Today Podcasts focusing on infertility, featuring insights from genetic counsellors and the writer and producer of an explosive genetics mystery sci-fi movie called ANYA (check it out, it’s very thought provoking).
Stay safe everyone.
Kind Regards,
Rich
Richard Lumb PhD
Founder & CEO
Front Line Genomics
J202, The Biscuit Factory, 100 Drummond Rd, London, SE16 4DG.
In-vitro fertilisation (IVF) is now regarded as a huge clinical success which has benefitted an estimated 16 million parents, at the time the development not only sparked moral outrage but led to political and legislative constraints. Patients undergoing IVF may be presented with numerous assisted reproductive treatments purportedly increasing the chances of pregnancy. Such commercialised “IVF add-ons” often come at high costs without clinical evidence of validity. Additionally, long-term studies of children born through IVF have historically been scarce and inconsistent in their data collection. This has meant that potential genetic predispositions, such as increased body fat composition and blood pressure, as well as congenital abnormalities long associated with IVF births, lack proof of causality.
With Preimplantation genetic testing mutated embryos are automatically discarded, whereas CRISPR could correct mutations to increase the number of viable embryos for implantation. Moreover, in instances where all embryos in a given cycle are destined to develop with severe or lethal mutations, CRISPR could bring success for otherwise doomed IVF treatments. Genetic screening programs offered to couples in hot-spot areas of carrier frequency of monogenic disorders have had huge success in alleviating regional disease burdens. Carried out since the 1970s these programs have altered the course of natural evolution, but few would dispute their benefits in preventing heritable disease transmission.
Mutations are as inevitable as death and taxes. Whilst age is considered one of the largest factors in de-novo mutation generation, it appears that these are inherited primarily from the paternal line. Thus, the paternal age of conception predominantly determines the mutation frequency inherited by children. Whereas advanced maternal age is not associated with mutagenic allele frequency but chromosomal abnormalities. The risk of aneuploidy rises steadily in mothers over the age of 26. Although embryos are screened for aneuploidy prior to implantation, with so many other factors simultaneously being screened the probability of having enough embryos remaining to allow for 50% rate of blastocyte development in-vitro are often fairly low.
Despite IVF being used routinely for over 40 years now, it’s not abundantly clear if, or how often, IVF may introduce genomic alternations or off-target affects in embryos. Likewise, scientists and clinicians are often unable to scrutinise changes produced through natural cellular processes including recombination and aging. So, it may be OK to do controlled experiments on using CRISPR to try and prevent multi-generational suffering. But, there has to be a long term investigation on the side effects of germline genome editing. Science has advanced a lot but still there are lot of things that are yet to be described or discovered by science. Trying to reduce human suffering should not give rise to new bigger sufferings and care must be taken not to create a Frankenstein.
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