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2024 Nobel Prize in Physiology or Medicine jointly to Victor Ambros and Gary Ruvkun for the discovery of microRNA and its role in post-transcriptional gene regulation
Reporter: Aviva Lev-Ari, PhD, RN
Updated 10/22/2024
The revolution in our understanding of transcriptional regulation and dark regions of the genome
The genome of higher eukaryotes are comprised of multiple exonic and intronic regions, with coding and noncoding DNA respectively. Much of the DNA sequence between exonic regions of genes, the sequences encoding the amino acids of a polypeptide, was considered either promoter regions regulating an exonic sequence or ‘junk DNA’, which had merely separated exons and their regulatory elements. It was not considered that this dark DNA or junk DNA was important in regulating transcription of genes. It was felt that most gene regulation occurred in promoter regions by response element factors which bound to specific sequences within these regions.
MicroRNA (miRNA), originally discovered in Caenorhabditis elegans, is found in most eukaryotes, including humans [1–3]. It is predicted that miRNA account for 1-5% of the human genome and regulate at least 30% of protein-coding genes [4–8]. To date, 940 distinct miRNAs molecules have been identified within the human genome [9–12] (http://microrna.sanger.ac.uk accessed July 20, 2010). Although little is currently known about the specific targets and biological functions of miRNA molecules thus far, it is evident that miRNA plays a crucial role in the regulation of gene expression controlling diverse cellular and metabolic pathways.
MiRNA are small, evolutionary conserved, single-stranded, non-coding RNA molecules that bind target mRNA to prevent protein production by one of two distinct mechanisms. Mature miRNA is generated through two-step cleavage of primary miRNA (pri-miRNA), which incorporates into the effector complex RNA-induced silencing complex (RISC). The miRNA functions as a guide by base-pairing with target mRNA to negatively regulate its expression. The level of complementarity between the guide and mRNA target determines which silencing mechanism will be employed; cleavage of target messenger RNA (mRNA) with subsequent degradation or translation inhibition
Fig. (1). MicroRNA maturation and function.
Figure. miRNA maturation and function. Source: Macfarlane LA, Murphy PR. MicroRNA: Biogenesis, Function and Role in Cancer. Curr Genomics. 2010 Nov;11(7):537-61. doi: 10.2174/138920210793175895.
The following is an interview in the journal Journal of Cellular Biology with Dr, Victor Ambros on his discovery of miRNA.
Source: Ambros V. Victor Ambros: the broad scope of microRNAs. Interview by Caitlin Sedwick. J Cell Biol. 2013 May 13;201(4):492-3. doi: 10.1083/jcb.2014pi. PMID: 23671307; PMCID: PMC3653358.
Once, we thought we understood all there was to know about how gene expression is regulated: A cell can tinker with the expression level of a given protein’s messenger RNA by modifying the activity, abundance, and type of transcription factors in the nucleus or with the RNA’s stability once it is made. But then came a surprising story about a short RNA in C. elegans called lin-4, which didn’t encode a protein but prevented expression of the protein encoded by another gene, lin-14, through antisense binding to lin-14 mRNA (1, 2). Today, we know that lin-4 was just the first example of a large number of small RNAs, called microRNAs, which regulate the expression of various other proteins in a similar way.
Victor Ambros, whose lab published that first story about lin-4, has been studying microRNAs (3, 4) and their regulation (5, 6) ever since, pushing forward our understanding of this powerful mechanism. We called him at his office at the University of Massachusetts Medical School to get some perspective on microRNAs and his career and to learn about some of the latest developments in his lab.
“That shared discovery is one of the most precious moments in my career.”
FROM FARM TO LAB TABLE
How did you end up doing a PhD with David Baltimore?
I was the first scientist in my family. My dad was an immigrant from Poland. He came to the States just after World War II and met my mom. They got married, moved to a farm in Vermont, and started farming. My siblings and I grew up amongst the cows and pigs and helped with the haying and cutting corn, stuff like that.
When I was about nine, I got interested in science, and after that I always wanted to be a scientist. I was an amateur astronomer; I built a telescope and started to imagine that I could actually do astronomy or physics as an occupation. But I quickly changed my mind when I reached college, in part because I realized that my math skills weren’t really up to the task of being a physicist and also because I discovered molecular biology and genetics and just fell in love with both subjects. David taught one of the advanced biology classes I took as an undergraduate at MIT, and that probably had some influence on my decision to work with him. After college, I worked as a technician in David’s lab for a year. I liked it a lot and stayed on in his lab when I entered graduate school at MIT. I was lucky because I had gotten a little bit of traction on a project and continued on that as a grad student, so I ended up finishing grad school fairly efficiently.
Had you any idea at the time what the nature of the lin-4 mutant was?
The assumption was that it was a protein product. I mean, nobody ever thought that there would be any other kind of regulator. There really wasn’t any reason to imagine that there were any other kinds of molecules necessary, other than proteins, to carry out everything that’s done in a cell—especially with regard to the regulation of gene expression. The complexity of gene regulation by proteins alone was so enormous that I never imagined—and nobody I knew imagined—that we needed to look for new kinds of regulatory molecules. The realization that lin-4 was antisense to the 3′-untranslated region of lin-14 was totally the result of communication between Gary and me. That shared discovery is one of the most precious moments in my career. But at the time I didn’t realize that this might be the first example of a general mechanism for regulating gene expression because I was prone to thinking that whatever I was studying in the worm was not generally applicable. It wasn’t until genome sequences were made available that the prevalence of this mechanism became clear.
THE RIGHT CONTEXT
You’ve moved to studying processes that modulate microRNA function…
One protein we’ve studied is called Nhl-2. It’s an example of an emerging class of proteins that can modulate, positively or negatively, the RNA-induced silencing complex (RISC) that inhibits mRNAs targeted by microRNAs. This class of genes may have either general effects on RISC activity or, in some cases, more specific effects. One area of interest in the lab right now is trying to understand the specific outcomes for the regulation of particular microRNAs. Do they always interact with all their targets, or is their activity on some targets promoted or inhibited at the expense of other targets? Can their interaction with certain targets be modified depending on context? We’re using genetic and genomic approaches to identify new modulatory cofactors.
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Victor Ambros was born in 1953 in Hanover, New Hampshire, USA. He received his PhD from Massachusetts Institute of Technology (MIT), Cambridge, MA, in 1979 where he also did postdoctoral research 1979-1985. He became a Principal Investigator at Harvard University, Cambridge, MA in 1985. He was Professor at Dartmouth Medical School from 1992-2007 and he is now Silverman Professor of Natural Science at the University of Massachusetts Medical School, Worcester, MA.
Gary Ruvkun was born in Berkeley, California, USA in 1952. He received his PhD from Harvard University in 1982. He was a postdoctoral fellow at Massachusetts Institute of Technology (MIT), Cambridge, MA, 1982-1985. He became a Principal Investigator at Massachusetts General Hospital and Harvard Medical School in 1985, where he is now Professor of Genetics.
This year’s Nobel Prize honors two scientists for their discovery of a fundamental principle governing how gene activity is regulated.
The information stored within our chromosomes can be likened to an instruction manual for all cells in our body. Every cell contains the same chromosomes, so every cell contains exactly the same set of genes and exactly the same set of instructions. Yet, different cell types, such as muscle and nerve cells, have very distinct characteristics. How do these differences arise? The answer lies in gene regulation, which allows each cell to select only the relevant instructions. This ensures that only the correct set of genes is active in each cell type.
Victor Ambros and Gary Ruvkun were interested in how different cell types develop. They discovered microRNA, a new class of tiny RNA molecules that play a crucial role in gene regulation. Their groundbreaking discovery revealed a completely new principle of gene regulation that turned out to be essential for multicellular organisms, including humans. It is now known that the human genome codes for over one thousand microRNAs. Their surprising discovery revealed an entirely new dimension to gene regulation. MicroRNAs are proving to be fundamentally important for how organisms develop and function.
Ambros and Ruvkun were interested in genes that control the timing of activation of different genetic programs, ensuring that various cell types develop at the right time. They studied two mutant strains of worms, lin-4 and lin-14, that displayed defects in the timing of activation of genetic programs during development. The laureates wanted to identify the mutated genes and understand their function. Ambros had previously shown that the lin-4 gene appeared to be a negative regulator of the lin-14 gene. However, how the lin-14 activity was blocked was unknown. Ambros and Ruvkun were intrigued by these mutants and their potential relationship and set out to resolve these mysteries.
Ambros and Ruvkun performed further experiments showing that the lin-4 microRNA turns off lin-14 by binding to the complementary sequences in its mRNA, blocking the production of lin-14 protein. A new principle of gene regulation, mediated by a previously unknown type of RNA, microRNA, had been discovered! The results were published in 1993 in two articles in the journal Cell.
Ruvkun cloned let-7, a second gene encoding a microRNA. The gene is conserved in evolution, and it is now known that microRNA regulation is universal among multicellular organisms.
Andrew Z. Fire and Craig C. Mello, awarded the Nobel Prize in 2006, described RNA interference, where specific mRNA-molecules are inactivated by adding double-stranded RNA to cells.
Mutations in one of the proteins required for microRNA production result in the DICER1 syndrome, a rare but severe syndrome linked to cancer in various organs and tissues.
Tweets and Re-Tweets of Tweets by @pharma_BI@AVIVA1950 at 2021 Virtual World Medical Innovation Forum, Mass General Brigham, Gene and Cell Therapy, VIRTUAL May 19–21, 2021
REAL TIME EVENT COVERAGE as PRESS by invitation from 2021 Virtual World Medical Innovation Forumat #WMIF2021 @MGBInnovation:
for sharing this screen capture of the impressive lineup of #GCT “Disruptive Dozen” panelists at #WMIF2021
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Aviva Lev-Ari
@AVIVA1950
· May 21
@MGBInnovation #WMIF Best Global event on Gene Cell Therapy covered in real time @AVIVA1950 @pharma_BI Disruptive Dozen technologies four are based on Gene Editing, AAV and non viral vector for drug delivery are included
PART 1: ALL THE TWEETS PRODUCED by @AVIVA1950 on May 21, 2021
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
The # of US patients with Parkinson’s Disease is expected to double over next 30 years. Penelope Hallett PhD, Co-Director of the Neuroregeneration Research Inst
Marcela Maus, MD PhD, are working to expand the reach of this transformative technology. #WMIF2021
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Mass General Brigham Innovation
@MGBInnovation
· 3h
Disruptive Dozen: 12 Technologies that Will Reinvent GCT #9. Building the Next Wave of CAR-T-cell Therapies #WMIF2021 #GCT #GeneAndCellTherapy #CellTherapy #CarT #DisruptiveDozen
and global colleagues at #WMIF2021. On Thursday, May 20, my colleagues and I will discuss the advantages of RNA-targeted medicines and how they might shape the future of medicine for patients.
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Mass General Brigham Innovation
@MGBInnovation
· May 10
Are you part of the @MassGenBrigham network and interested in #GeneAndCellTherapy? Join us at the World Medical Innovation Forum on 5/19-5/21. Register today! https://worldmedicalinnovation.org/register/ #WMIF2021
Incredible opportunity to get up to speed with the most innovative technologies in medicine ! Gene and cell therapy are revolutionizing healthcare ! #WMIF2021#MedTwitter
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Mass General Brigham Innovation
@MGBInnovation
· May 11
#WMIF2021 is an opportunity for innovators from around the globe to meet, explore, challenge, and reflect on the issues influencing the adoption of novel technologies in #healthcare. Register now to join the conversation: https://worldmedicalinnovation.org/register/
Currently, the only cure for some common blood disorders is a bone marrow transplant, which can be risky. Now, gene therapies are also in the works, including a CRISPR-based #genetherapy being tested in clinical trials with encouraging early results. #WMIF2021
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Mass General Brigham Innovation
@MGBInnovation
· 3h
Disruptive Dozen: 12 Technologies that Will Reinvent GCT #2. A Genetic Fix for Two Common Blood Disorders #WMIF2021 #GCT #GeneAndCellTherapy #BloodDisorders #DisruptiveDozen
Researchers have pinpointed key genes involved in cholesterol and lipid metabolism that represent promising targets for new cholesterol-lowering treatments. #WMIF2021
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Mass General Brigham Innovation
@MGBInnovation
· 3h
Disruptive Dozen: 12 Technologies that Will Reinvent GCT #1. A New Generation of Cholesterol-Loweing Therapies #WMIF2021 #GCT #GeneAndCellTherapy #DisruptiveDozen
I really enjoyed this remarkable panel #WMIF2021. Thank you Meredith Fisher for moderating and thank you David, Bob and Kush for openly sharing your big picture view
Variability, delays, manufacturing as an afterthought make #GCT challenging from an investment POV — need to rethink the ecosystem and drive efficiency, invest in tech innovation says Bob Nelson ARCH Venture Partners
We need to change the scale and scope of how #GCT is advancing from discovery to development — systematization critical. Can’t have thousands of one-off therapies say early-stage investors. Major mis-match between where things are now and what could be.
Today I moderated a panel on Gene and Cell Therapy Delivery, Perfecting the Technology. We highlighted non-viral delivery technologies as key enablers of gene therapy and editing. Learn more: https://lnkd.in/d-Xqzqh#WMIF2021
Congratulations to the 2021 Innovation Discovery Grants winners: @lynchielydia, Peter Sage, @GrishchukL, Benjamin Kleinstiver, Petr Baranov, announced at the #WMIF2021. It’s exciting to see the range of breakthrough research in #geneticdisease at @MassGenBrigham…
for sharing this screen capture of the impressive lineup of #GCT “Disruptive Dozen” panelists at #WMIF2021
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Aviva Lev-Ari
@AVIVA1950
· May 21
@MGBInnovation #WMIF Best Global event on Gene Cell Therapy covered in real time @AVIVA1950 @pharma_BI Disruptive Dozen technologies four are based on Gene Editing, AAV and non viral vector for drug delivery are included
PART 1: ALL THE TWEETS PRODUCED by @AVIVA1950 on May 20, 2021
Bob Brown, PhD CSO, EVP of R&D, Dicerna small molecule vs capacity of nanoparticles to deliver therapeutics quantity for more molecule is much larger CNS delivery most difficult
Jeannie Lee, MD, PhD Molecular Biologist, MGH Prof Genetics, HMS 200 disease X chromosome unlock for neurological genetic diseases: Rett Syndrome, autism spectrum disorders female model vs male mice model restore own protein
Suneet Varma Global President of Rare Disease, Pfizer review of protocols and CGT for Hemophilia Pfizer: You can’t buy Time With MIT Pfizer is developing a model for Hemophilia CGT treatment
Gallia Levy, MD, PhD CMO, Spark Therapeutics Hemophilia CGT is the highest potential for Global access logistics in underdev countries working with NGOs practicality of the Tx Roche reached 120 Counties great to be part of the Roche
Theresa Heggie CEO, Freeline Therapeutics Safety concerns, high burden of treatment CGT has record of safety and risk/benefit adoption of Tx functional cure CGT is potent Tx relative small quantity of protein needs be delivered
Suneet Varma Global President of Rare Disease, Pfizer Gene therapy at Pfizer small, large molecule and CGT – spectrum of choice allowing Hemophilia patients to marry 1/3 internal 1/3 partnership 1/3 acquisitions review of protocols
Ron Renaud CEO, Translate Bio What strain of Flu vaccine will come back in the future when people do not use masks. AAV vectors small transcript size fit reach cytoplasm more development coming
Melissa Moore Chief Scientific Officer, Moderna 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
Lindsey Baden, MD Director, Clinical Research, Division of Infectious Diseases, BWH Associate Professor, HMS In vivo delivery process regulatory for new opportunities for same platform new indication using multi valence vaccines
Melissa Moore Chief Scientific Officer, Moderna 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
Ron Renaud CEO, Translate Bio 1.6 Billion doses produced rare disease monogenic correct mRNA like CF multiple mutation infection disease and oncology applications
Melissa Moore CSO, Moderna mRNA vaccine 98% efficacy for Pfizer and Moderna more then 10 years 2015 mRNA was ready (ZIKA, RSV), as the proteine is identify manufacturing temp less of downside in the future ability to store at Ref
Richard Wang, PhD CEO, Fosun Kite Biotechnology Co. Ltd Possibilities to be creative and capitalize the new technologies for new drug Support of the ecosystem by funding new companies Autologous in patients differences cost challenge
Tian Xu, PhD Vice President, Westlake University ICH Chinese FDA -r regulation similar to the US Difference is the population recruitment, in China patients are active participants Dev of transposome non-viral methods, price
Alvin Luk, PhD CEO, Neuropath Therapeutics Monogenic rare disease with clear genomic target Increase of 30% in patient enrollment Regulatory reform approval is 60 days no delay
We’re excited to attend this week’s #WMIF2021 to talk all things cell and genetic therapies. Join our Chief of VCGT Bastiano Sanna tomorrow at 9:50am EDT for a discussion on the promise of cell therapies for type 1 diabetes. Register now! https://bit.ly/3otngYd
John Fish, Board Chair, Brigham Health, Chairman & CEO, Suffolk on the Novartis Main Stage to introduce the “Collaboration is Key: GCT R&D of the Future” fireside chat with Jay Bradner, MD, President, NIBR
Thomas VanCott, PhD, Chief Technology & Strategy Officer, Catalent Cell & Gene Therapy, says that time, improvements and scaling up in manufacturing will lead to allogeneic cell therapies. He recognizes that upfront costs are high, but will decrease in the long term #WMIF2021
Today Lisa Michaels, Editas CMO, will participate in the panel “Gene Editing – Achieving Therapeutic Mainstream” at the World Medical Innovation Forum #WMIF2021 in Boston. For those attending, be sure to tune in!
, views GCT as the ultimate precision medicine. AI, machine learning, and data science comprise one of the big disruptive forces that will address misdiagnosis, smooth out workflow, reduce cost and enhance recovery. #WMIF2021
CSO Laura Sepp-Lorenzino, PhD, in our “GCT Delivery | Perfecting the Technology” panel this afternoon! #WMIF2021
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Intellia Therapeutics
@intelliatweets
· 6h
Today, Intellia CSO, @LauraSeppLore will be participating in the World Medical Innovation Forum’s panel on Gene and Cell Therapy Delivery, Perfecting the Technology. #WMIF2021 @MGBInnovation. Click here to learn more: https://worldmedicalinnovation.org
is back with us this afternoon sharing a First Look at “Versatile Polymer-Based Nanocarriers for Targeted Therapy and Immunomodulation.” #WMIF2021#GCT#geneandcelltherapy
VP of Clinical Development, Manasi Jaiman, during the “Diabetes | Grand Challenge” panel today. #WMIF2021
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ViaCyte
@ViaCyte
· 8h
Join us at #WMIF2021 today! Our own Manasi Jaiman, VP, Clinical Development, will participate in the Diabetes: Grand Challenge panel to discuss regenerative medicine approaches for T1D utilizing stem-cell derived islet cell replacement therapy.
, discusses how GCT is in the embryonic phase. Bayer is ready to treat its first Parkinson’s patient, and is exploring therapeutic technologies to treat diseases with single gene defects #WMIF2021
Today Lisa Michaels, Editas CMO, will participate in the panel “Gene Editing – Achieving Therapeutic Mainstream” at the World Medical Innovation Forum #WMIF2021 in Boston. For those attending, be sure to tune in! @MassGenBrigham https://bit.ly/3hx1XTV #geneediting #biotechnology
to discuss the current state of CAR-T and its future prospects. These conversations are important for the development of potential #CART therapies. #WMIF2021
‘s #WMIF2021 — Thanks to the MGB team for facilitating a great discussion!
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Mass General Brigham Innovation
@MGBInnovation
· 7h
Overview of our #mRNA Vaccines panel today, highlighting improved manufacturing capabilities & potential for #personalizedmedicine. Thank you to Lindsey Baden @bwh_id & panelists Kate Bingham, SV Health Investors, Melissa Moore @moderna_tx and Ron Renaud @TranslateBio #WMIF2021
investigators are ready to give you an early preview of their #GCT research in the First Look sessions at #WMIF2021. Exciting opportunities to dramatically change how disease is treated!
Our “Rare and Ultra Rare Diseases | GCT Breaks Through” panelists on the role of family organizations & patient advocacy groups in moving us forward on the regulatory side – “It’s absolutely essential” #WMIF2021
Congratulations! Lydia Lynch PhD, Brigham and Women’s Hospital receives an Innovation Discovery Grant for “Generating Superior ‘Killers’ for Adoptive Cell Therapy in Cancer” at #WMIF2021.
Looking forward to the Diabetes Grand Challenge and how #GCT could help millions of people. Read about what facing this disease and how cell therapies could lessen the burden from Manasi Jaiman, MD, VP, Clinical Development
Today is Day 2 of the World Medical Innovation Forum. Which panel you are most excited to see today? Reply and let us know! #WMIF2021 https://worldmedicalinnovation.org/agenda/
Cell and gene therapies hold promising potential for rare disease, blood cancers, and viral diseases. Register for #WMIF21 to hear about our work to pioneer cutting-edge science across our pipeline to advance breakthroughs that change patients’ lives: https://on.pfizer.com/3f3CGzj
Congratulations! Peter Sage PhD, Brigham and Women’s Hospital receives an Innovation Discovery Grant for “Novel Strategies to Enhance Tfr Treatment of Autoimmunity” at #WMIF2021
Congratulations! Yulia Grishchuk PhD, Massachusetts General Hospital, receives an Innovation Discovery Grant for “AAV-Based Gene Replacement Therapy Improves Targeting and Clinical Outcomes in a Childhood CNS Disorder” at #WMIF2021
Congratulations! Jinjun Shi, PhD, Brigham and Women’s Hospital, receives an Innovation Discovery Grant for “Long-Lasting mRNA Therapy for Genetic Disorders” at #WMIF2021
Final thoughts from “Benign Blood Disorders” panelists on academic/industry collaboration — the pace of #innovation is incredibly exciting, and I think it will be even faster together. #WMIF2021
Congratulations! Benjamin Kleinstiver PhD, Massachusetts General Hospital, receives an Innovation Discovery Grant for “Towards a Permanent Genetic Cure for Spinal Muscular Atrophy” at #WMIF2021
FDA’s Peter Marks, at #WMIF2021, notes # of INDs for gene therapies was flat in 2020 vs. 2019. But the fact IND submissions didn’t decline, he said, is a sign of how strong the gene therapy field is, given pandemic’s disruption.
Melissa Moore/Moderna- one advantage of mRNA is ability to do multivalent vaccines she said. She said they are already testing multivalent covid vaccines in clinical trials & testing flu vaccines. #wmif2021
Kate Bingham/SV Health & former head of UK Vaccine Taskforce: they haven’t seen escape variants in UK yet she said. mRNA is quickest platform to address escape variants probably. Needle delivery w/ supply cold chain has been the challenge. Deploying 3 vaccines in UK #WMIF2021
, notes that the science behind gene cell therapies is converging with technological development. How therapies are brought to market is still the question, as there is no roadmap when reimagining medicine #WMIF2021
Melissa Moore/Moderna: clear advantage of mRNA vaccine is how quickly we can manufacture the vaccines. Downsides- need 2store at low temperatures & limited shelflife 4storage in refrigerator. I know that both companies [Moderna, Pfizer/BioNTech] r working 2change this #wmif2021
We’re committed to addressing the unmet needs of people living with rare genetic diseases. Our SVP, External Innovation and Strategic Alliances, Leah Bloom, discusses the promise #genetherapy holds for communities impacted by rare diseases during #WMIF2021.
Speed of vaccination is critical to prevent escape variants says Kate Bingham, SV Health Investors, UK, at #WMIF2021, exploring what’s next for the technology w panel led by Lindsey Baden MD,
for sharing this screen capture of the impressive lineup of #GCT “Disruptive Dozen” panelists at #WMIF2021
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Aviva Lev-Ari
@AVIVA1950
· May 21
@MGBInnovation #WMIF Best Global event on Gene Cell Therapy covered in real time @AVIVA1950 @pharma_BI Disruptive Dozen technologies four are based on Gene Editing, AAV and non viral vector for drug delivery are included
PART 1: ALL THE TWEETS PRODUCED by @AVIVA1950 on May 19, 2021
Thomas VanCott, PhD Global Head of Product Dev, Gene & Cell Therapy, Catalent 2/3 autologous 1/3 allogeneic CAR-T high doses scale up is not done today logistics issues centralized vs decentralized allogeneic are health donors
Ropa Pike, Director, Enterprise Science & Partnerships, Thermo FIsher Scientific Centralized biopharma industry is moving to decentralized models site specific license
Rahul Singhvi, ScD CEO and Co-Founder, National Resilience, Inc. Investment company in platforms to be shared by start ups in CGT. Production cost of allogeneic: cost of quality 30% reagents 30% cell 30% Test is very expensive
Oladapo Yeku, MD, PhD Clinical Assistant in Medicine, MGH Outstanding moderator and most gifted panel on solid tumor success window of opportunities studies
Knut Niss, PhD CTO, Mustang Bio tumor hot start in 12 month clinical trial solid tumors Combination therapy will be an experimental treatment long journey checkpoint inhibitors to be used in combination maintenance
Barbra Sasu, PhD CSO, Allogene T cell response at prostate cancer tumor specific cytokine tumor specific signals move from solid to metastatic cell type for easier infiltration
Jennifer Brogdon Executive Director, Head of Cell Therapy Research, Exploratory Immuno-Oncology, NIBR 2017 CAR-T first approval M&A and research collaborations TCR tumor specific antigens avoid tissue toxicity
Jay Short, PhD Chairman, CEO, Cofounder, BioAlta, Inc. Tumor type is not enough for R&D therapeutics other organs are involved in periphery difficult to penetrate solid tumors biologics activated in the tumor only, positive changes
Stefan Hendriks Global Head, Cell & Gene, Novartis Confirmation the effectiveness of CAR-T therapies, 1 year response to 5 years 26 months Patient not responding a lot to learn Patient after 8 months of chemo can be helped by CAR-T
Jeffrey Infante, MD , Oncology, Janssen R&D Direct effect with intra-tumor single injection with right payload Platform approach Prime with 1 and Boost with 2 – not yet experimented with Do not have the data at trial
Nino Chiocca, MD, PhD Neurosurgeon-in-Chief BWH, HMS Oncolytic therapy DID NOT WORK Pancreatic Cancer and Glioblastoma Intra-tumoral heterogeniety hinders success Oncolytic VIRUSES – “coldness” GADD-34 20,000 GBM 40,000 pancreatic
Loic Vincent, PhD Head of Oncology Drug Discovery Unit, Takeda Classification of Patients by prospective response type id UNKNOWN yet, population of patients require stratification
Loic Vincent, PhD Head of Oncology Drug Discovery Unit, Takeda R&D in collaboration with Academic Vaccine platform to explore different payload IV administration may not bring sufficient concentration to the tumor is administer IV
Nino Chiocca, MD, PhD Neurosurgeon-in-Chief and Chairman, Neurosurgery, BWH Harvey W. Cushing Professor of Neurosurgery, HMS Challenges of manufacturing at Amgen what are they?
David Reese, MD Executive Vice President, R&D , Amgen Inter lesion injection of agent vs systemic therapeutics cold tumors immune resistant render them immune susptible Oncolytic virus is a Mono therapy addressing the unknown
David Reese, MD Executive Vice President, Research and Development, Amgen Inter lesion injection of agent vs systemic therapeutics cold tumors immune resistant render them immune suseptible Oncolytic virus is a Mono therapy
Robert Coffin, PhD Chief R&D Officer, Replimune 2002 in UK promise in oncolytic therapy GNCSF Phase III melanoma 2015 M&A with Amgen oncolytic therapy remains non effecting on immune response data is key for commercialization
Ann Silk, MD Physician, Dana Farber-Brigham and Women’s Cancer Center, HMS Which person gets oncolytics virus if patient has immune supression due to other indications Safety of oncolytic virus greater than Systemic treatment
Marianne De Backer/Bayer on post M&A & company culture: They acquired AskBio & thought about how to preserve their freedom so they could continue to operate. Bayer decided to keep them independent & so they can operate at arm’s length. #wmif2021
Merit Cudkowicz, MD Chief of Neurology, MGH ALS – Man 1in 300, Women 1 in 400, next decade increase 7% 10% ALS is heredity 160 pharma in ALS space diagnosis is late 1/3 of people are not diagnosed active community for clinical trials @pharma_BI@AVIVA1950
Adam Koppel, MD, PhD Managing Director, Bain Capital Life Sciences What acquirers are looking for?? What is the next generation vs what is real where is the industry going?
Debby Baron, Worldwide Business Development, Pfizer Scalability and manufacturing regulatory conversations, clinical programs safety in parallel to planning getting drug to patients
Marianne De Backer, PhD Head of Strategy, BD & Licensing, Bayer Absolute Leadership: Gene editing, gene therapy, via acquisition and alliances Operating model of the acquired company discussed acquired continue independence
Sean Nolan Board Chairman, Encoded Therapeutics & Affinia Executive Chairman Jaguar Gene Therapy Istari Oncology As acquiree multiple M&A acquirer looks at integration and cultures companies Traditional integration vs acquisition
Debby Baron, Worldwide Business Development, Pfizer CGT is an important area Pfizer is active looking for innovators, advancing forward programs of innovation with the experience Pfizer has internally
Marianne De Backer, PhD Head of Strategy, Business Development & Licensing, and Member of the Executive Committee, Bayer Absolute Leadership in Gene editing, gene therapy, via acquisition and strategic alliance
Manny Simons, PhD CEO, Akouos 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
Mathew Pletcher, PhD SVP, Head of Gene Therapy Research and Technical Operations, Astellas Continue to explore large animal guinea pig not the mice, not primates (ethical issues) for understanding immunogenicity and immune response
Mathew Pletcher, PhD SVP, Head of Gene Therapy Research and Technical Operations, Astellas Work with diseases poorly understood, collaborations needs example of existing: DMD is a great example explain dystrophin share placedo data
Rick Modi CEO, Affinia Therapeutics Speed R&D Speed better gene construct get to clinic with better design vs ASAP Data sharing clinical experience patients selection, vector selection, mitigation, patient type specific
Dave Lennon, PhD President, Novartis Gene Therapies big pharma therapeutics not one drug across Tx areas: cell, gene iodine therapy collective learning infrastructure development Acquisitions growth # applications for scaling
Rick Modi CEO, Affinia Therapeutics Copy, paste EDIT from product A to B novel vectors variant of vector coder optimization choice of indication is critical exploration on larger populations Speed to R&D to better gene construct get
Louise Rodino-Klapac, PhD EVP, Chief Scientific Officer, Sarepta Therapeutics AV based platform 15 years in development 1 disease indication vs more than one indication stereotype, analytics as hurdle 1st was 10 years 2nd was 3 years
Katherine High, MD President, Therapeutics, AskBio Three drugs approved in Europe in the CGT Regulatory Infrastructure CGT drug approval – as new class of therapeutics Participants investigators, regulators, patients i.e., MDM
Peter Marks, MD, PhD Director, Center for Biologics Evaluation and Research, FDA Immune modulators Immunotherapy Genome editing can make use of viral vectors future technologies nanoparticles and liposome encapsulation 50% more staff
Peter Marks, MD, PhD Director, Center for Biologics Evaluation and Research, FDA Recover Work load for the pandemic Gene Therapies IND application remained flat Rare diseases urgency remains Guidance T-Cell therapy vs Regulation
Peter Marks, MD, PhD Director, Center for Biologics Evaluation and Research, FDA June 2020 belief that vaccine challenge manufacture scaling up FDA did not predicted the efficacy of mRNA vaccine vs other approaches expected to work
Jim Holland CEO, http://Backcountry.com Parkinson patient Constraints by regulatory on participation in clinical trial wish to take Information dissemination is critical
Patricia Musolino, MD, PhD Co-Director Pediatric Stroke and Cerebrovascular Program What is the Power of One – the impact that a patient can have on their own destiny connecting with other participants in same trial can be beneficial
Barbara Lavery Chief Program Officer, ACGT Foundation Patient has the knowledge of the symptoms and recording all input needed for diagnosis by multiple clinicians Early application for CGT
Jack Hogan Patient, MEE Constraints by regulatory on participation in #clinicaltrials advance stage is approved participation Patients to determine the level of #risk they wish to take
Barbara Lavery Chief Program Officer, ACGT Foundation Advocacy agency beginning of work Global Genes educational content and out reach to access the information
Dave Lennon, PhD President, Novartis Gene Therapies Modality one time intervention, long duration of impart, reimbursement, ecosystem FDA works by indications and risks involved, Standards manufacturing payments over time payers
Dave Lennon, PhD President, Novartis Gene Therapies Promise of CGT realized, what part? #FDA role and interaction in CGT #Manufacturing aspects which is critical
Julian Harris, MD Partner, Deerfield Hope that CGT emerging, how therapies work, #neuro, #muscular, #ocular, #genetic diseases of #liver and of #heart revolution for the industry 900 #IND application 25 approvals #Economic driver
Luk Vandenberghe, PhD Grousbeck Family Chair, Gene Therapy, MEE Associate Professor, Ophthalmology, HMS #Pharmacology#Gene-Drug, Interface academic centers and industry many CGT drugs emerged in Academic center
Ravi Thadhani, MD CAO, Mass General Brigham Professor, Medicine and Faculty Dean, HMS Role of #academia special to spear head the #Polygenic#therapy – multiple #genes involved, #plug-play #delivery
The field of #genetherapy is growing. New therapies will come to market for rare and chronic diseases, and new therapies will drive scientific innovation and economic growth. #WMIF2021 (2/6)
In our First Look sessions clinicians/researchers from Harvard-affiliated hospitals highlight the potential of their research & new technologies. Next we’ll hear from Khalid Shah PhD, Vice Chair of Research
Tomorrow is Day 1 of #WMIF2021! Hear from the world-renowned CEOs, investors, clinicians and scientists bringing game-changing discoveries and insights to #GCT. Register to attend today: https://worldmedicalinnovation.org/register/
‘s World Medical Innovation Forum this week, discussing the future of #genetherapy. Here are our five predictions for where the industry is headed. #WMIF2021 (1/6)
explains at #WMIF2021 why the first FDA-approved gene therapy for inherited disease was for an inherited retinal degeneration, and what lessons have been learned from the success of that treatment.
Together with @BayerPharma, we are pleased to be part of #WMIF2021, organized by @MassGenBrigham. This year’s event focuses on the transformative potential of #cellandgene therapy (#GCT).
“We are more committed to our mission than ever before – laser-focused on realizing the transformative potential of #genetherapy for patients.” – Dave Lennon, President, during #WMIF2021
Patricia Musolino, MD PhD, Co-Director Pediatric Stroke and Cerebrovascular Program at MGH, discusses her work developing #genetherapy treatments for cerebral genetic vasculopathies #GCT #geneandcelltherapy #WMIF2021
chair Dr. Joan Miller moderates a panel on AAV gene therapy featuring director of Inherited Retinal Disorders Service and Ocular Genomics Institute, Dr. Eric Pierce.
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Our “AAV Success Studies | Retinal Dystrophy | Spinal Muscular Atrophy” panelists have taken the stage. #WMIF2021 @MassEyeAndEar @REGENXBIO @spark_tx @NovartisGene
We are proud sponsors of the Virtual World Medical Innovation Forum (#WMIF2021). This year’s program will focus on the impact of gene and cell therapy as a way to potentially advance quality patient care, reduce cost and improve outcomes. Learn more:
Jonathan Kraft introducing #wmif2021 session with Pfizer CSO & president of R&D Mikael Dolsten and MGH oncologist & chair of MGH Cancer Center Daniel Haber.
president Dave Lennon & Deerfield partner Julian Harris having a “fireside chat.” Dave/Novartis: sees gene therapy as driver for economy generating need for highly skilled workers Incl manufacturing
Kite Pharma CEO (Gilead subsidiary) Christi Shaw said there are 120 biopharma companies working on CAR-T cell therapy & they are continuing to look for new partnerships. She also mentioned logistical challenges currently getting to Israel & helping patients there. #WMIF2021
FDA’s Dir of Center for Biologics Evaluation & Research Peter Marks interviewed by Vicki Sato- chairwoman of Vir Biotechnology, ex Vertex president & ex Biogen VP Research. Around June ’20, started 2c progress in covid vaccines w/ enough candidates moving forward #WMIF2021 1/n
“Once you work on cell and gene therapy, its really hard to go back and work on anything else” says moderator Marcela Maus, MD PhD in our “CAR-T | Lessons Learned | What’s Next” panel #WMIF2021#GCT#geneandcelltherapy
Ex Merck president R&D Roger Perlmutter is now Eikon Therapeutics CEO & is on #WMIF2021 oncolytic virus in cancer panel w/Amgen EVP R&D David Reese, ex BioVex CTO (T-VEC inventor
, join our leaders for panels and presentations discussing what’s next for #genetherapy and the key trends shaping the industry as it evolves. #WMIF2021https://bit.ly/3eYYls4
Dolsten/Pfizer discussed covid vaccines and real world evidence study in Israel. Was sole provider of vaccines in Israel. 95%-98% efficacy replicated in real world. Well above 90% efficacy in asymptomatic disease. #wmif2021
ICYMI: An illustration depicting the “AAV Delivery” panel discussion about advances in the area of #AAVGeneTherapy delivery. Thank you to the panelists from
Casey Maguire PhD, Associate Professor of Neurology, at the podium to present his work developing improved #genetherapy vectors. #WMIF2021 “First Look: Enhanced Gene Delivery and Immunoevasion of AAV Vectors without Capsid Modification”
Casey Maguire PhD, Associate Professor of Neurology, at the podium to present his work developing improved #genetherapy vectors. #WMIF2021 “First Look: Enhanced Gene Delivery and Immunoevasion of AAV Vectors without Capsid Modification”
Mikael Dolsten, MD PhD, CSO & President, Worldwide Research, Development and Medical @pfizer takes the stage for a Fireside Chat, moderated by @MGHCancerCenter Daniel Haber, MD, PhD. “Pfizer’s Future in Cell and Gene Therapy” #WMIF2021
Dave Lennon/Novartis: manufacturing has been a roadblock for many cell & gene therapy companies. Expects to see more investments earlier. Engineering advances will unlock scale & address bigger & bigger patient populations. Oppty to ID patients early #WMIF2021
Marianne De Backer/Bayer on post M&A & company culture: They acquired AskBio & thought about how to preserve their freedom so they could continue to operate. Bayer decided to keep them independent & so they can operate at arm’s length. #wmif2021
Ken Custer/Eli Lilly-said they’re relatively new in cell & gene therapy. They invested in 1 of Sean Nolan’s (ex AveXis CEO) new companies,Jaguar Gene Therapy. Lilly’s legacy in neuroscience is noted & bought Prevail last yr. Clinical trial w/ Parkinson’s w/GBA1 mutation #wmif2021
, was the first in the U.S. to be approved for FDA gene therapy surgery. In 2018 he underwent therapy to treat retinitis pigmentosa by having a synthetic gene inserted into his retina. With improved eyesight he can now play sports #WMIF2021
The acquisition market in #GCT: looking for breakthroughs for patients, technologies for intractable diseases, manufacturing expertise, pioneering companies with deep experience — all for “the modality of the future”. M&A panel at #WMIF2021
Christi Shaw/Kite Pharma: Only 4 out of 10 patients eligible for CAR-T are being referred for CAR-T cell therapy by oncologists. The other 6 out of 10, referred to palliative care only. Consistency of manufacturing is also very important. #wmif2021 1/n
Marianne De Backer/Bayer on post M&A & company culture: They acquired AskBio & thought about how to preserve their freedom so they could continue to operate. Bayer decided to keep them independent & so they can operate at arm’s length. #wmif2021
2021 Virtual World Medical Innovation Forum, Mass General Brigham, Gene and Cell Therapy, VIRTUAL May 19–21, 2021
The 2021 Virtual World Medical Innovation Forum will focus on the growing impact of gene and cell therapy. Senior healthcare leaders from all over look to shape and debate the area of gene and cell therapy. Our shared belief: no matter the magnitude of change, responsible healthcare is centered on a shared commitment to collaborative innovation–industry, academia, and practitioners working together to improve patients’ lives.
About the World Medical Innovation Forum
Mass General Brigham is pleased to present the World Medical Innovation Forum (WMIF) virtual event Wednesday, May 19 – Friday, May 21. This interactive web event features expert discussions of gene and cell therapy (GCT) and its potential to change the future of medicine through its disease-treating and potentially curative properties. The agenda features 150+ executive speakers from the healthcare industry, venture, startups, life sciences manufacturing, consumer health and the front lines of care, including many Harvard Medical School-affiliated researchers and clinicians. The annual in-person Forum will resume live in Boston in 2022. The World Medical Innovation Forum is presented by Mass General Brigham Innovation, the global business development unit supporting the research requirements of 7,200 Harvard Medical School faculty and research hospitals including Massachusetts General, Brigham and Women’s, Massachusetts Eye and Ear, Spaulding Rehab and McLean Hospital. Follow us on Twitter: twitter.com/@MGBInnovation
Accelerating the Future of Medicine with Gene and Cell Therapy What Comes Next
Co-Chairs identify the key themes of the Forum – set the stage for top GCT opportunities, challenges, and where the field might take medicine in the future. Moderator: Susan Hockfield, PhD
President Emerita and Professor of Neuroscience, MIT
Hope that CGT emerging, how the therapies work, neuro, muscular, ocular, genetic diseases of liver and of heart revolution for the industry 900 IND application 25 approvals Economic driver Skilled works, VC disease. Modality one time intervention, long duration of impart, reimbursement, ecosystem to be built around CGT
FDA works by indications and risks involved, Standards and expectations for streamlining manufacturing, understanding of process and products
payments over time payers and Innovators relations Moderator: Julian Harris, MD
Partner, Deerfield
Promise of CGT realized, what part?
FDA role and interaction in CGT
Manufacturing aspects which is critical Speaker: Dave Lennon, PhD
President, Novartis Gene Therapies
Hope that CGT emerging, how the therapies work, neuro, muscular, ocular, genetic diseases of liver and of heart revolution for the industry 900 IND application 25 approvals Economic driver Skilled works, VC disease. Modality one time intervention, long duration of impart, reimbursement, ecosystem to be built around CGT
FDA works by indications and risks involved, Standards and expectations for streamlining manufacturing, understanding of process and products
payments over time payers and Innovators relations
GCT development for rare diseases is driven by patient and patient-advocate communities. Understanding their needs and perspectives enables biomarker research, the development of value-driving clinical trial endpoints and successful clinical trials. Industry works with patient communities that help identify unmet needs and collaborate with researchers to conduct disease natural history studies that inform the development of biomarkers and trial endpoints. This panel includes patients who have received cutting-edge GCT therapy as well as caregivers and patient advocates. Moderator: Patricia Musolino, MD, PhD
Co-Director Pediatric Stroke and Cerebrovascular Program, MGH
Assistant Professor of Neurology, HMS
What is the Power of One – the impact that a patient can have on their own destiny by participating in Clinical Trials Contacting other participants in same trial can be beneficial Speakers: Jack Hogan
Parkinson patient Constraints by regulatory on participation in clinical trial advance stage is approved participation Patients to determine the level of risk they wish to take Information dissemination is critical Barbara Lavery
Chief Program Officer, ACGT Foundation
Advocacy agency beginning of work Global Genes educational content and out reach to access the information
Patient has the knowledge of the symptoms and recording all input needed for diagnosis by multiple clinicians Early application for CGTDan Tesler
Clinical Trial Patient, BWH/DFCC
Experimental Drug clinical trial patient participation in clinical trial is very important to advance the state of scienceSarah Beth Thomas, RN
Professional Development Manager, BWH
Outcome is unknown, hope for good, support with resources all advocacy groups,
Process at FDA generalize from 1st entry to rules more generalizable Speaker: Peter Marks, MD, PhD
Director, Center for Biologics Evaluation and Research, FDA
Last Spring it became clear that something will work a vaccine by June 2020 belief that enough candidates the challenge manufacture enough and scaling up FDA did not predicted the efficacy of mRNA vaccine vs other approaches expected to work
Recover Work load for the pandemic will wean & clear, Gene Therapies IND application remained flat in the face of the pandemic Rare diseases urgency remains Consensus with industry advisory to get input gene therapy Guidance T-Cell therapy vs Regulation best thinking CGT evolve speedily flexible gained by Guidance
Immune modulators, Immunotherapy Genome editing can make use of viral vectors future technologies nanoparticles and liposome encapsulation
big pharma has portfolios of therapeutics not one drug across Tx areas: cell, gene iodine therapy
collective learning infrastructure features manufacturing at scale early in development Acquisitions strategy for growth # applications for scaling Rick Modi
CEO, Affinia Therapeutics
Copy, paste EDIT from product A to B novel vectors leverage knowledge varient of vector, coder optimization choice of indication is critical exploration on larger populations Speed to R&D and Speed to better gene construct get to clinic with better design vs ASAP
Data sharing clinical experience with vectors strategies patients selection, vector selection, mitigation, patient type specific Louise Rodino-Klapac, PhD
AAV based platform 15 years in development same disease indication vs more than one indication stereotype, analytics as hurdle 1st was 10 years 2nd was 3 years
Safety to clinic vs speed to clinic, difference of vectors to trust
Recent AAV gene therapy product approvals have catalyzed the field. This new class of therapies has shown the potential to bring transformative benefit to patients. With dozens of AAV treatments in clinical studies, all eyes are on the field to gauge its disruptive impact.
The panel assesses the largest challenges of the first two products, the lessons learned for the broader CGT field, and the extent to which they serve as a precedent to broaden the AAV modality.
Is AAV gene therapy restricted to genetically defined disorders, or will it be able to address common diseases in the near term?
Lessons learned from these first-in-class approvals.
Challenges to broaden this modality to similar indications.
Reflections on safety signals in the clinical studies?
Tissue types additional administrations, tech and science, address additional diseases, more science for photoreceptors a different tissue type underlying pathology novelties in last 10 years
Laxterna success to be replicated platform, paradigms measurement visual improved
More science is needed to continue develop vectors reduce toxicity,
AAV can deliver different cargos reduce adverse events improve vectorsRon Philip
Chief Operating Officer, Spark Therapeutics
The first retinal gene therapy, voretigene neparvovec-rzyl (Luxturna, Spark Therapeutics), was approved by the FDA in 2017.Meredith Schultz, MD
Executive Medical Director, Lead TME, Novartis Gene Therapies
Impact of cell therapy beyond muscular dystrophy, translational medicine, each indication, each disease, each group of patients build platform unlock the promise
Monitoring for Safety signals real world evidence remote markers, home visits, clinical trial made safer, better communication of information
AAV a complex driver in Pharmacology durable, vector of choice, administer in vitro, gene editing tissue specificity, pharmacokinetics side effects and adverse events manufacturability site variation diversify portfolios,
This panel will address the advances in the area of AAV gene therapy delivery looking out the next five years. Questions that loom large are: How can biodistribution of AAV be improved? What solutions are in the wings to address immunogenicity of AAV? Will patients be able to receive systemic redosing of AAV-based gene therapies in the future? What technical advances are there for payload size? Will the cost of manufacturing ever become affordable for ultra-rare conditions? Will non-viral delivery completely supplant viral delivery within the next five years?What are the safety concerns and how will they be addressed? Moderators: Xandra Breakefield, PhD
Ataxia requires therapy targeting multiple organ with one therapy, brain, spinal cord, heart several IND, clinical trials in 2022Mathew Pletcher, PhD
SVP, Head of Gene Therapy Research and Technical Operations, Astellas
Work with diseases poorly understood, collaborations needs example of existing: DMD is a great example explain dystrophin share placedo data
Continue to explore large animal guinea pig not the mice, not primates (ethical issues) for understanding immunogenicity and immune response Manny Simons, PhD
CEO, Akouos
AAV Therapy for the fluid of the inner ear, CGT for the ear vector accessible to surgeons translational work on the inner ear for gene therapy right animal model
Biology across species nerve ending in the cochlea
engineer out of the caspid, lowest dose possible, get desired effect by vector use, 2022 new milestones
The GCT M&A market is booming – many large pharmas have made at least one significant acquisition. How should we view the current GCT M&A market? What is its impact of the current M&A market on technology development? Are these M&A trends new are just another cycle? Has pharma strategy shifted and, if so, what does it mean for GCT companies? What does it mean for patients? What are the long-term prospects – can valuations hold up? Moderator: Adam Koppel, MD, PhD
Managing Director, Bain Capital Life Sciences
What acquirers are looking for??
What is the next generation vs what is real where is the industry going? Speakers:
Debby Baron,
Worldwide Business Development, Pfizer
CGT is an important area Pfizer is active looking for innovators, advancing forward programs of innovation with the experience Pfizer has internally
Scalability and manufacturing regulatory conversations, clinical programs safety in parallel to planning getting drug to patients
ALS – Man 1in 300, Women 1 in 400, next decade increase 7%
10% ALS is heredity 160 pharma in ALS space, diagnosis is late 1/3 of people are not diagnosed, active community for clinical trials Challenges: disease heterogeneity cases of 10 years late in diagnosis. Clinical Trials for ALS in Gene Therapy targeting ASO1 protein therapies FUS gene struck youngsters
Cell therapy for ACTA2 Vasculopathy in the brain and control the BP and stroke – smooth muscle intima proliferation. Viral vector deliver aiming to change platform to non-viral delivery rare disease , gene editing, other mutations of ACTA2 gene target other pathway for atherosclerosis
Oncolytic viruses represent a powerful new technology, but so far an FDA-approved oncolytic (Imlygic) has only occurred in one area – melanoma and that what is in 2015. This panel involves some of the protagonists of this early success story. They will explore why and how Imlygic became approved and its path to commercialization. Yet, no other cancer indications exist for Imlygic, unlike the expansion of FDA-approved indication for immune checkpoint inhibitors to multiple cancers. Why? Is there a limitation to what and which cancers can target? Is the mode of administration a problem?
No other oncolytic virus therapy has been approved since 2015. Where will the next success story come from and why? Will these therapies only be beneficial for skin cancers or other easily accessible cancers based on intratumoral delivery?
The panel will examine whether the preclinical models that have been developed for other cancer treatment modalities will be useful for oncolytic viruses. It will also assess the extent pre-clinical development challenges have slowed the development of OVs. Moderator: Nino Chiocca, MD, PhD
Neurosurgeon-in-Chief and Chairman, Neurosurgery, BWH
Harvey W. Cushing Professor of Neurosurgery, HMS
Challenges of manufacturing at Amgen what are they? Speakers: Robert Coffin, PhD
Chief Research & Development Officer, Replimune
2002 in UK promise in oncolytic therapy GNCSF
Phase III melanoma 2015 M&A with Amgen
oncolytic therapy remains non effecting on immune response
data is key for commercialization
do not belief in systemic therapy achieve maximum immune response possible from a tumor by localized injection Roger Perlmutter, MD, PhD
Chairman, Merck & Co.
response rates systemic therapy like PD1, Keytruda, OPTIVA well tolerated combination of Oncolytic with systemic
Physician, Dana Farber-Brigham and Women’s Cancer Center
Assistant Professor of Medicine, HMS
Which person gets oncolytics virus if patient has immune suppression due to other indications
Safety of oncolytic virus greater than Systemic treatment
series biopsies for injected and non injected tissue and compare Suspect of hot tumor and cold tumors likely to have sme response to agent unknown all potential
There are currently two oncolytic virus products on the market, one in the USA and one in China. As of late 2020, there were 86 clinical trials 60 of which were in phase I with just 2 in Phase III the rest in Phase I/II or Phase II. Although global sales of OVs are still in the ramp-up phase, some projections forecast OVs will be a $700 million market by 2026. This panel will address some of the major questions in this area:
What regulatory challenges will keep OVs from realizing their potential? Despite the promise of OVs for treating cancer only one has been approved in the US. Why has this been the case? Reasons such have viral tropism, viral species selection and delivery challenges have all been cited. However, these are also true of other modalities. Why then have oncolytic virus approaches not advanced faster and what are the primary challenges to be overcome?
Will these need to be combined with other agents to realize their full efficacy and how will that impact the market?
Why are these companies pursuing OVs while several others are taking a pass?
In 2020 there were a total of 60 phase I trials for Oncolytic Viruses. There are now dozens of companies pursuing some aspect of OV technology. This panel will address:
How are small companies equipped to address the challenges of developing OV therapies better than large pharma or biotech?
Will the success of COVID vaccines based on Adenovirus help the regulatory environment for small companies developing OV products in Europe and the USA?
Is there a place for non-viral delivery and other immunotherapy companies to engage in the OV space? Would they bring any real advantages?
Systemic delivery Oncolytic Virus IV delivery woman in remission
Collaboration with Regeneron
Data collection: Imageable reporter secretable reporter, gene expression
Field is intense systemic oncolytic delivery is exciting in mice and in human, response rates are encouraging combination immune stimulant, check inhibitors
Few areas of potential cancer therapy have had the attention and excitement of CAR-T. This panel of leading executives, developers, and clinician-scientists will explore the current state of CAR-T and its future prospects. Among the questions to be addressed are:
Is CAR-T still an industry priority – i.e. are new investments being made by large companies? Are new companies being financed? What are the trends?
What have we learned from first-generation products, what can we expect from CAR-T going forward in novel targets, combinations, armored CAR’s and allogeneic treatment adoption?
Early trials showed remarkable overall survival and progression-free survival. What has been observed regarding how enduring these responses are?
Most of the approvals to date have targeted CD19, and most recently BCMA. What are the most common forms of relapses that have been observed?
Is there a consensus about what comes after these CD19 and BCMA trials as to additional targets in liquid tumors? How have dual-targeted approaches fared?
The potential application of CAR-T in solid tumors will be a game-changer if it occurs. The panel explores the prospects of solid tumor success and what the barriers have been. Questions include:
How would industry and investor strategy for CAR-T and solid tumors be characterized? Has it changed in the last couple of years?
Does the lack of tumor antigen specificity in solid tumors mean that lessons from liquid tumor CAR-T constructs will not translate well and we have to start over?
Whether due to antigen heterogeneity, a hostile tumor micro-environment, or other factors are some specific solid tumors more attractive opportunities than others for CAR-T therapy development?
Given the many challenges that CAR-T faces in solid tumors, does the use of combination therapies from the start, for example, to mitigate TME effects, offer a more compelling opportunity.
Executive Director, Head of Cell Therapy Research, Exploratory Immuno-Oncology, NIBR
2017 CAR-T first approval
M&A and research collaborations
TCR tumor specific antigens avoid tissue toxicity Knut Niss, PhD
CTO, Mustang Bio
tumor hot start in 12 month clinical trial solid tumors , theraties not ready yet. Combination therapy will be an experimental treatment long journey checkpoint inhibitors to be used in combination maintenance Lipid tumor Barbra Sasu, PhD
CSO, Allogene
T cell response at prostate cancer
tumor specific
cytokine tumor specific signals move from solid to metastatic cell type for easier infiltration
Where we might go: safety autologous and allogeneic Jay Short, PhD
Chairman, CEO, Cofounder, BioAlta, Inc.
Tumor type is not enough for development of therapeutics other organs are involved in the periphery
difficult to penetrate solid tumors biologics activated in the tumor only, positive changes surrounding all charges, water molecules inside the tissue acidic environment target the cells inside the tumor and not outside
The modes of GCT manufacturing have the potential of fundamentally reordering long-established roles and pathways. While complexity goes up the distance from discovery to deployment shrinks. With the likelihood of a total market for cell therapies to be over $48 billion by 2027, groups of products are emerging. Stem cell therapies are projected to be $28 billion by 2027 and non-stem cell therapies such as CAR-T are projected be $20 billion by 2027. The manufacturing challenges for these two large buckets are very different. Within the CAR-T realm there are diverging trends of autologous and allogeneic therapies and the demands on manufacturing infrastructure are very different. Questions for the panelists are:
Help us all understand the different manufacturing challenges for cell therapies. What are the trade-offs among storage cost, batch size, line changes in terms of production cost and what is the current state of scaling naïve and stem cell therapy treatment vs engineered cell therapies?
For cell and gene therapy what is the cost of Quality Assurance/Quality Control vs. production and how do you think this will trend over time based on your perspective on learning curves today?
Will point of care production become a reality? How will that change product development strategy for pharma and venture investors? What would be the regulatory implications for such products?
How close are allogeneic CAR-T cell therapies? If successful what are the market implications of allogenic CAR-T? What are the cost implications and rewards for developing allogeneic cell therapy treatments?
Global Head of Product Development, Gene & Cell Therapy, Catalent
2/3 autologous 1/3 allogeneic CAR-T high doses and high populations scale up is not done today quality maintain required the timing logistics issues centralized vs decentralized allogeneic are health donors innovations in cell types in use improvements in manufacturing
China embraced gene and cell therapies early. The first China gene therapy clinical trial was in 1991. China approved the world’s first gene therapy product in 2003—Gendicine—an oncolytic adenovirus for the treatment of advanced head and neck cancer. Driven by broad national strategy, China has become a hotbed of GCT development, ranking second in the world with more than 1,000 clinical trials either conducted or underway and thousands of related patents. It has a booming GCT biotech sector, led by more than 45 local companies with growing IND pipelines.
In late 1990, a T cell-based immunotherapy, cytokine-induced killer (CIK) therapy became a popular modality in the clinic in China for tumor treatment. In early 2010, Chinese researchers started to carry out domestic CAR T trials inspired by several important reports suggested the great antitumor function of CAR T cells. Now, China became the country with the most registered CAR T trials, CAR T therapy is flourishing in China.
The Chinese GCT ecosystem has increasingly rich local innovation and growing complement of development and investment partnerships – and also many subtleties.
This panel, consisting of leaders from the China GCT corporate, investor, research and entrepreneurial communities, will consider strategic questions on the growth of the gene and cell therapy industry in China, areas of greatest strength, evolving regulatory framework, early successes and products expected to reach the US and world market. Moderator: Min Wu, PhD
Managing Director, Fosun Health Fund
What are the area of CGT in China, regulatory similar to the US Speakers: Alvin Luk, PhD
CEO, Neuropath Therapeutics
Monogenic rare disease with clear genomic target
Increase of 30% in patient enrollment
Regulatory reform approval is 60 days no delayPin Wang, PhD
CSO, Jiangsu Simcere Pharmaceutical Co., Ltd.
Similar starting point in CGT as the rest of the World unlike a later starting point in other biologicalRichard Wang, PhD
CEO, Fosun Kite Biotechnology Co., Ltd
Possibilities to be creative and capitalize the new technologies for innovating drug
Support of the ecosystem by funding new companie allowing the industry to be developed in China
Autologous in patients differences cost challengeTian Xu, PhD
Vice President, Westlake University
ICH committee and Chinese FDA -r regulation similar to the US
Difference is the population recruitment, in China patients are active participants in skin disease
Active in development of transposome
Development of non-viral methods, CRISPR still in D and transposome
In China price of drugs regulatory are sensitive Shunfei Yan, PhD
The COVID vaccine race has propelled mRNA to the forefront of biomedicine. Long considered as a compelling modality for therapeutic gene transfer, the technology may have found its most impactful application as a vaccine platform. Given the transformative industrialization, the massive human experience, and the fast development that has taken place in this industry, where is the horizon? Does the success of the vaccine application, benefit or limit its use as a therapeutic for CGT?
How will the COVID success impact the rest of the industry both in therapeutic and prophylactic vaccines and broader mRNA lessons?
How will the COVID success impact the rest of the industry both on therapeutic and prophylactic vaccines and broader mRNA lessons?
Beyond from speed of development, what aspects make mRNA so well suited as a vaccine platform?
Will cost-of-goods be reduced as the industry matures?
How does mRNA technology seek to compete with AAV and other gene therapy approaches?
Many years of mRNA pivoting for new diseases, DARPA, nucleic Acids global deployment of a manufacturing unit on site where the need arise Elan Musk funds new directions at Moderna
How many mRNA can be put in one vaccine: Dose and tolerance to achieve efficacy
45 days for Personalized cancer vaccine one per patient
Hemophilia has been and remains a hallmark indication for the CGT. Given its well-defined biology, larger market, and limited need for gene transfer to provide therapeutic benefit, it has been at the forefront of clinical development for years, however, product approval remains elusive. What are the main hurdles to this success? Contrary to many indications that CGT pursues no therapeutic options are available to patients, hemophiliacs have an increasing number of highly efficacious treatment options. How does the competitive landscape impact this field differently than other CGT fields? With many different players pursuing a gene therapy option for hemophilia, what are the main differentiators? Gene therapy for hemophilia seems compelling for low and middle-income countries, given the cost of currently available treatments; does your company see opportunities in this market? Moderator: Nancy Berliner, MD
Safety concerns, high burden of treatment CGT has record of safety and risk/benefit adoption of Tx functional cure CGT is potent Tx relative small quantity of protein needs be delivered
Potency and quality less quantity drug and greater potency
risk of delivery unwanted DNA, capsules are critical
analytics is critical regulator involvement in potency definition
Director, Center for Rare Neurological Diseases, MGH
Associate Professor, Neurology, HMS
Single gene disorder NGS enable diagnosis, DIagnosis to Treatment How to know whar cell to target, make it available and scale up Address gap: missing components Biomarkers to cell types lipid chemistry cell animal biology
crosswalk from bone marrow matter
New gene discovered that causes neurodevelopment of stagnant genes Examining new Biology cell type specific biomarkers
The American Diabetes Association estimates 30 million Americans have diabetes and 1.5 million are diagnosed annually. GCT offers the prospect of long-sought treatment for this enormous cohort and their chronic requirements. The complexity of the disease and its management constitute a grand challenge and highlight both the potential of GCT and its current limitations.
Islet transplantation for type 1 diabetes has been attempted for decades. Problems like loss of transplanted islet cells due to autoimmunity and graft site factors have been difficult to address. Is there anything different on the horizon for gene and cell therapies to help this be successful?
How is the durability of response for gene or cell therapies for diabetes being addressed? For example, what would the profile of an acceptable (vs. optimal) cell therapy look like?
Advanced made, Patient of Type 1 Outer and Inner compartments of spheres (not capsule) no immune suppression continuous secretion of enzyme Insulin independence without immune suppression
Volume to have of-the-shelf inventory oxegenation in location lymphatic and vascularization conrol the whole process modular platform learning from others
Keep eyes open, waiting the Pandemic to end and enable working back on all the indications
Portfolio of MET, Mimi Emerging Therapies
Learning from the Pandemic – operationalize the practice science, R&D leaders, new collaboratives at NIH, FDA, Novartis
Pursue programs that will yield growth, tropic diseases with Gates Foundation, Rising Tide pods for access CGT within Novartis Partnership with UPenn in Cell Therapy
Cost to access to IP from Academia to a Biotech CRISPR accessing few translations to Clinic
Protein degradation organization constraint valuation by parties in a partnership
Novartis: nuclear protein lipid nuclear particles, tamplate for Biotech to collaborate
Game changing: 10% of the Portfolio, New frontiers human genetics in Ophthalmology, CAR-T, CRISPR, Gene Therapy Neurological and payloads of different matter
The Voice of Dr. Seidman – Her abstract is cited below
The ultimate opportunity presented by discovering the genetic basis of human disease is accurate prediction and disease prevention. To enable this achievement, genetic insights must enable the identification of at-risk
individuals prior to end-stage disease manifestations and strategies that delay or prevent clinical expression. Genetic cardiomyopathies provide a paradigm for fulfilling these opportunities. Hypertrophic cardiomyopathy (HCM) is characterized by left ventricular hypertrophy, diastolic dysfunction with normal or enhanced systolic performance and a unique histopathology: myocyte hypertrophy, disarray and fibrosis. Dilated cardiomyopathy (DCM) exhibits enlarged ventricular volumes with depressed systolic performance and nonspecific histopathology. Both HCM and DCM are prevalent clinical conditions that increase risk for arrhythmias, sudden death, and heart failure. Today treatments for HCM and DCM focus on symptoms, but none prevent disease progression. Human molecular genetic studies demonstrated that these pathologies often result from dominant mutations in genes that encode protein components of the sarcomere, the contractile unit in striated muscles. These data combined with the emergence of molecular strategies to specifically modulate gene expression provide unparalleled opportunities to silence or correct mutant genes and to boost healthy gene expression in patients with genetic HCM and DCM. Many challenges remain, but the active and vital efforts of physicians, researchers, and patients are poised to ensure success.
Cyprus Island, kidney disease by mutation causing MUC1 accumulation and death BRD4780 molecule that will clear the misfolding proteins from the kidney organoids: pleuripotent stem cells small molecule developed for applications in the other cell types in brain, eye, gene mutation build mechnism for therapy clinical models transition from Academia to biotech
One of the most innovative segments in all of healthcare is the development of GCT driven therapies for rare and ultra-rare diseases. Driven by a series of insights and tools and funded in part by disease focused foundations, philanthropists and abundant venture funding disease after disease is yielding to new GCT technology. These often become platforms to address more prevalent diseases. The goal of making these breakthroughs routine and affordable is challenged by a range of issues including clinical trial design and pricing.
What is driving the interest in rare diseases?
What are the biggest barriers to making breakthroughs ‘routine and affordable?’
What is the role of retrospective and prospective natural history studies in rare disease? When does the expected value of retrospective disease history studies justify the cost?
Related to the first question, what is the FDA expecting as far as controls in clinical trials for rare diseases? How does this impact the collection of natural history data?
The power of GCT to cure disease has the prospect of profoundly improving the lives of patients who respond. Planning for a disruption of this magnitude is complex and challenging as it will change care across the spectrum. Leading chief executives shares perspectives on how the industry will change and how this change should be anticipated. Moderator: Meg Tirrell
Senior Health and Science Reporter, CNBC
CGT becoming staple therapy what are the disruptors emerging Speakers: Lisa Dechamps
SVP & Chief Business Officer, Novartis Gene Therapies
Reimagine medicine with collaboration at MGH, MDM condition in children
The Science is there, sustainable processes and systems impact is transformational
Value based pricing, risk sharing Payers and Pharma for one time therapy with life span effect
Head, Pharmaceuticals Research & Development, Bayer AG
CGT – 2016 and in 2020 new leadership and capability
Disease Biology and therapeutics
Regenerative Medicine: CGT vs repair building pipeline in ophthalmology and cardiovascular
During Pandemic: Deliver Medicines like Moderna, Pfizer – collaborations between competitors with Government Bayer entered into Vaccines in 5 days, all processes had to change access innovations developed over decades for medical solutions
GCT represents a large and growing market for novel therapeutics that has several segments. These include Cardiovascular Disease, Cancer, Neurological Diseases, Infectious Disease, Ophthalmology, Benign Blood Disorders, and many others; Manufacturing and Supply Chain including CDMO’s and CMO’s; Stem Cells and Regenerative Medicine; Tools and Platforms (viral vectors, nano delivery, gene editing, etc.). Bayer’s pharma business participates in virtually all of these segments. How does a Company like Bayer approach the development of a portfolio in a space as large and as diverse as this one? How does Bayer approach the support of the production infrastructure with unique demands and significant differences from its historical requirements? Moderator:
EVP, Pharmaceuticals, Head of Cell & Gene Therapy, Bayer AG
CGT will bring treatment to cure, delivery of therapies
Be a Leader repair, regenerate, cure
Technology and Science for CGT – building a portfolio vs single asset decision criteria development of IP market access patients access acceleration of new products
Bayer strategy: build platform for use by four domains
Gener augmentation
Autologeneic therapy, analytics
Gene editing
Oncology Cell therapy tumor treatment: What kind of cells – the jury is out
Of 23 product launch at Bayer no prediction is possible some high some lows
Gene delivery uses physical, chemical, or viral means to introduce genetic material into cells. As more genetically modified therapies move closer to the market, challenges involving safety, efficacy, and manufacturing have emerged. Optimizing lipidic and polymer nanoparticles and exosomal delivery is a short-term priority. This panel will examine how the short-term and long-term challenges are being tackled particularly for non-viral delivery modalities. Moderator: Natalie Artzi, PhD
Gene editing was recognized by the Nobel Committee as “one of gene technology’s sharpest tools, having a revolutionary impact on life sciences.” Introduced in 2011, gene editing is used to modify DNA. It has applications across almost all categories of disease and is also being used in agriculture and public health.
Today’s panel is made up of pioneers who represent foundational aspects of gene editing. They will discuss the movement of the technology into the therapeutic mainstream.
Successes in gene editing – lessons learned from late-stage assets (sickle cell, ophthalmology)
When to use what editing tool – pros and cons of traditional gene-editing v. base editing. Is prime editing the future? Specific use cases for epigenetic editing.
When we reach widespread clinical use – role of off-target editing – is the risk real? How will we mitigate? How practical is patient-specific off-target evaluation?
There are several dozen companies working to develop gene or cell therapies for Sickle Cell Disease, Beta Thalassemia, and Fanconi Anemia. In some cases, there are enzyme replacement therapies that are deemed effective and safe. In other cases, the disease is only managed at best. This panel will address a number of questions that are particular to this class of genetic diseases:
What are the pros and cons of various strategies for treatment? There are AAV-based editing, non-viral delivery even oligonucleotide recruitment of endogenous editing/repair mechanisms. Which approaches are most appropriate for which disease?
How can companies increase the speed of recruitment for clinical trials when other treatments are available? What is the best approach to educate patients on a novel therapeutic?
How do we best address ethnic and socio-economic diversity to be more representative of the target patient population?
How long do we have to follow up with the patients from the scientific, patient’s community, and payer points of view? What are the current FDA and EMA guidelines for long-term follow-up?
Where are we with regards to surrogate endpoints and their application to clinically meaningful endpoints?
What are the emerging ethical dilemmas in pediatric gene therapy research? Are there challenges with informed consent and pediatric assent for trial participation?
Are there differences in reimbursement policies for these different blood disorders? Clearly durability of response is a big factor. Are there other considerations?
Oligonucleotide drugs have recently come into their own with approvals from companies such as Biogen, Alnylam, Novartis and others. This panel will address several questions:
How important is the delivery challenge for oligonucleotides? Are technological advancements emerging that will improve the delivery of oligonucleotides to the CNS or skeletal muscle after systemic administration?
Will oligonucleotides improve as a class that will make them even more effective? Are further advancements in backbone chemistry anticipated, for example.
Will oligonucleotide based therapies blaze trails for follow-on gene therapy products?
Are small molecules a threat to oligonucleotide-based therapies?
Beyond exon skipping and knock-down mechanisms, what other roles will oligonucleotide-based therapies take mechanistically — can genes be activating oligonucleotides? Is there a place for multiple mechanism oligonucleotide medicines?
Are there any advantages of RNAi-based oligonucleotides over ASOs, and if so for what use?
What is occurring in the GCT venture capital segment? Which elements are seeing the most activity? Which areas have cooled? How is the investment market segmented between gene therapy, cell therapy and gene editing? What makes a hot GCT company? How long will the market stay frothy? Some review of demographics — # of investments, sizes, etc. Why is the market hot and how long do we expect it to stay that way? Rank the top 5 geographic markets for GCT company creation and investing? Are there academic centers that have been especially adept at accelerating GCT outcomes? Do the business models for the rapid development of coronavirus vaccine have any lessons for how GCT technology can be brought to market more quickly? Moderator: Meredith Fisher, PhD
The promise of stem cells has been a highlight in the realm of regenerative medicine. Unfortunately, that promise remains largely in the future. Recent breakthroughs have accelerated these potential interventions in particular for treating neurological disease. Among the topics the panel will consider are:
Stem cell sourcing
Therapeutic indication growth
Genetic and other modification in cell production
Cell production to final product optimization and challenges
The dynamics of venture/PE investing and IPOs are fast evolving. What are the drivers – will the number of investors grow will the size of early rounds continue to grow? How is this reflected in GCT target areas, company design, and biotech overall? Do patients benefit from these trends? Is crossover investing a distinct class or a little of both? Why did it emerge and what are the characteristics of the players? Will SPACs play a role in the growth of the gene and cell therapy industry. What is the role of corporate investment arms eg NVS, Bayer, GV, etc. – has a category killer emerged? Are we nearing the limit of what the GCT market can absorb or will investment capital continue to grow unabated? Moderator: Roger Kitterman
Nearly one hundred senior Mass General Brigham Harvard faculty contributed to the creation of this group of twelve GCT technologies that they believe will breakthrough in the next two years. The Disruptive Dozen identifies and ranks the GCT technologies that will be available on at least an experimental basis to have the chance of significantly improving health care. 11:35 AM – 11:45 AM
Computer connection to the iCloud of WordPress.com FROZE completely at 10:30AM EST and no file update was possible. COVERAGE OF MAY 21, 2021 IS RECORDED BELOW FOLLOWING THE AGENDA BY COPY AN DPASTE OF ALL THE TWEETS I PRODUCED ON MAY 21, 2021 8:30 AM – 8:55 AM
What is occurring in the GCT venture capital segment? Which elements are seeing the most activity? Which areas have cooled? How is the investment market segmented between gene therapy, cell therapy and gene editing? What makes a hot GCT company? How long will the market stay frothy? Some review of demographics — # of investments, sizes, etc. Why is the market hot and how long do we expect it to stay that way? Rank the top 5 geographic markets for GCT company creation and investing? Are there academic centers that have been especially adept at accelerating GCT outcomes? Do the business models for the rapid development of coronavirus vaccine have any lessons for how GCT technology can be brought to market more quickly? Moderator: Meredith Fisher, PhD
The promise of stem cells has been a highlight in the realm of regenerative medicine. Unfortunately, that promise remains largely in the future. Recent breakthroughs have accelerated these potential interventions in particular for treating neurological disease. Among the topics the panel will consider are:
Stem cell sourcing
Therapeutic indication growth
Genetic and other modification in cell production
Cell production to final product optimization and challenges
The dynamics of venture/PE investing and IPOs are fast evolving. What are the drivers – will the number of investors grow will the size of early rounds continue to grow? How is this reflected in GCT target areas, company design, and biotech overall? Do patients benefit from these trends? Is crossover investing a distinct class or a little of both? Why did it emerge and what are the characteristics of the players? Will SPACs play a role in the growth of the gene and cell therapy industry. What is the role of corporate investment arms eg NVS, Bayer, GV, etc. – has a category killer emerged? Are we nearing the limit of what the GCT market can absorb or will investment capital continue to grow unabated? Moderator: Roger Kitterman
Nearly one hundred senior Mass General Brigham Harvard faculty contributed to the creation of this group of twelve GCT technologies that they believe will breakthrough in the next two years. The Disruptive Dozen identifies and ranks the GCT technologies that will be available on at least an experimental basis to have the chance of significantly improving health care. 11:35 AM – 11:45 AM
The co-chairs convene to reflect on the insights shared over the three days. They will discuss what to expect at the in-person GCT focused May 2-4, 2022 World Medical Innovation Forum.
The co-chairs convene to reflect on the insights shared over the three days. They will discuss what to expect at the in-person GCT focused May 2-4, 2022 World Medical Innovation Forum.Christine Seidman, MD
Cyprus Island, kidney disease by mutation causing MUC1 accumulation and death BRD4780 molecule that will clear the misfolding proteins from the kidney organoids: pleuripotent stem cells small molecule developed for applications in the other cell types in brain, eye, gene mutation build mechnism for therapy clinical models transition from Academia to biotech
One of the most innovative segments in all of healthcare is the development of GCT driven therapies for rare and ultra-rare diseases. Driven by a series of insights and tools and funded in part by disease focused foundations, philanthropists and abundant venture funding disease after disease is yielding to new GCT technology. These often become platforms to address more prevalent diseases. The goal of making these breakthroughs routine and affordable is challenged by a range of issues including clinical trial design and pricing.
What is driving the interest in rare diseases?
What are the biggest barriers to making breakthroughs ‘routine and affordable?’
What is the role of retrospective and prospective natural history studies in rare disease? When does the expected value of retrospective disease history studies justify the cost?
Related to the first question, what is the FDA expecting as far as controls in clinical trials for rare diseases? How does this impact the collection of natural history data?
The power of GCT to cure disease has the prospect of profoundly improving the lives of patients who respond. Planning for a disruption of this magnitude is complex and challenging as it will change care across the spectrum. Leading chief executives shares perspectives on how the industry will change and how this change should be anticipated. Moderator: Meg Tirrell
Senior Health and Science Reporter, CNBC
CGT becoming staple therapy what are the disruptors emerging Speakers: Lisa Dechamps
SVP & Chief Business Officer, Novartis Gene Therapies
Reimagine medicine with collaboration at MGH, MDM condition in children
The Science is there, sustainable processes and systems impact is transformational
Value based pricing, risk sharing Payers and Pharma for one time therapy with life span effect
Head, Pharmaceuticals Research & Development, Bayer AG
CGT – 2016 and in 2020 new leadership and capability
Disease Biology and therapeutics
Regenerative Medicine: CGT vs repair building pipeline in ophthalmology and cardiovascular
During Pandemic: Deliver Medicines like Moderna, Pfizer – collaborations between competitors with Government Bayer entered into Vaccines in 5 days, all processes had to change access innovations developed over decades for medical solutions
GCT represents a large and growing market for novel therapeutics that has several segments. These include Cardiovascular Disease, Cancer, Neurological Diseases, Infectious Disease, Ophthalmology, Benign Blood Disorders, and many others; Manufacturing and Supply Chain including CDMO’s and CMO’s; Stem Cells and Regenerative Medicine; Tools and Platforms (viral vectors, nano delivery, gene editing, etc.). Bayer’s pharma business participates in virtually all of these segments. How does a Company like Bayer approach the development of a portfolio in a space as large and as diverse as this one? How does Bayer approach the support of the production infrastructure with unique demands and significant differences from its historical requirements? Moderator:
EVP, Pharmaceuticals, Head of Cell & Gene Therapy, Bayer AG
CGT will bring treatment to cure, delivery of therapies
Be a Leader repair, regenerate, cure
Technology and Science for CGT – building a portfolio vs single asset decision criteria development of IP market access patients access acceleration of new products
Bayer strategy: build platform for use by four domains
Gener augmentation
Autologeneic therapy, analytics
Gene editing
Oncology Cell therapy tumor treatment: What kind of cells – the jury is out
Of 23 product launch at Bayer no prediction is possible some high some lows
Gene delivery uses physical, chemical, or viral means to introduce genetic material into cells. As more genetically modified therapies move closer to the market, challenges involving safety, efficacy, and manufacturing have emerged. Optimizing lipidic and polymer nanoparticles and exosomal delivery is a short-term priority. This panel will examine how the short-term and long-term challenges are being tackled particularly for non-viral delivery modalities. Moderator: Natalie Artzi, PhD
Gene editing was recognized by the Nobel Committee as “one of gene technology’s sharpest tools, having a revolutionary impact on life sciences.” Introduced in 2011, gene editing is used to modify DNA. It has applications across almost all categories of disease and is also being used in agriculture and public health.
Today’s panel is made up of pioneers who represent foundational aspects of gene editing. They will discuss the movement of the technology into the therapeutic mainstream.
Successes in gene editing – lessons learned from late-stage assets (sickle cell, ophthalmology)
When to use what editing tool – pros and cons of traditional gene-editing v. base editing. Is prime editing the future? Specific use cases for epigenetic editing.
When we reach widespread clinical use – role of off-target editing – is the risk real? How will we mitigate? How practical is patient-specific off-target evaluation?
There are several dozen companies working to develop gene or cell therapies for Sickle Cell Disease, Beta Thalassemia, and Fanconi Anemia. In some cases, there are enzyme replacement therapies that are deemed effective and safe. In other cases, the disease is only managed at best. This panel will address a number of questions that are particular to this class of genetic diseases:
What are the pros and cons of various strategies for treatment? There are AAV-based editing, non-viral delivery even oligonucleotide recruitment of endogenous editing/repair mechanisms. Which approaches are most appropriate for which disease?
How can companies increase the speed of recruitment for clinical trials when other treatments are available? What is the best approach to educate patients on a novel therapeutic?
How do we best address ethnic and socio-economic diversity to be more representative of the target patient population?
How long do we have to follow up with the patients from the scientific, patient’s community, and payer points of view? What are the current FDA and EMA guidelines for long-term follow-up?
Where are we with regards to surrogate endpoints and their application to clinically meaningful endpoints?
What are the emerging ethical dilemmas in pediatric gene therapy research? Are there challenges with informed consent and pediatric assent for trial participation?
Are there differences in reimbursement policies for these different blood disorders? Clearly durability of response is a big factor. Are there other considerations?
Oligonucleotide drugs have recently come into their own with approvals from companies such as Biogen, Alnylam, Novartis and others. This panel will address several questions:
How important is the delivery challenge for oligonucleotides? Are technological advancements emerging that will improve the delivery of oligonucleotides to the CNS or skeletal muscle after systemic administration?
Will oligonucleotides improve as a class that will make them even more effective? Are further advancements in backbone chemistry anticipated, for example.
Will oligonucleotide based therapies blaze trails for follow-on gene therapy products?
Are small molecules a threat to oligonucleotide-based therapies?
Beyond exon skipping and knock-down mechanisms, what other roles will oligonucleotide-based therapies take mechanistically — can genes be activating oligonucleotides? Is there a place for multiple mechanism oligonucleotide medicines?
Are there any advantages of RNAi-based oligonucleotides over ASOs, and if so for what use?
Computer connection to the iCloud of WordPress.com FROZE completely at 10:30AM EST and no file update was possible. COVERAGE OF MAY 21, 2021 IS RECORDED BELOW FOLLOWING THE AGENDA BY COPY AN DPASTE OF ALL THE TWEETS I PRODUCED ON MAY 21, 2021
What is occurring in the GCT venture capital segment? Which elements are seeing the most activity? Which areas have cooled? How is the investment market segmented between gene therapy, cell therapy and gene editing? What makes a hot GCT company? How long will the market stay frothy? Some review of demographics — # of investments, sizes, etc. Why is the market hot and how long do we expect it to stay that way? Rank the top 5 geographic markets for GCT company creation and investing? Are there academic centers that have been especially adept at accelerating GCT outcomes? Do the business models for the rapid development of coronavirus vaccine have any lessons for how GCT technology can be brought to market more quickly? Moderator: Meredith Fisher, PhD
Partner, Mass General Brigham Innovation Fund
Strategies, success what changes are needed in the drug discovery process Speakers:
Bring disruptive frontier as a platform with reliable delivery CGT double knock out disease cure all change efficiency and scope human centric vs mice centered right scale of data converted into therapeutics acceleratetion
Innovation in drugs 60% fails in trial because of Toxicology system of the future deal with big diseases
Moderna is an example in unlocking what is inside us Microbiome and beyond discover new drugs epigenetics
Manufacturing change is not a new clinical trial FDA need to be presented with new rethinking for big innovations Drug pricing cheaper requires systematization How to systematically scaling up systematize the discovery and the production regulatory innovations
The promise of stem cells has been a highlight in the realm of regenerative medicine. Unfortunately, that promise remains largely in the future. Recent breakthroughs have accelerated these potential interventions in particular for treating neurological disease. Among the topics the panel will consider are:
Stem cell sourcing
Therapeutic indication growth
Genetic and other modification in cell production
Cell production to final product optimization and challenges
Director, Neuroregeneration Research Institute, McLean
Professor, Neurology and Neuroscience, MGH, HMS
Opportunities in the next generation of the tactical level Welcome the oprimism and energy level of all Translational medicine funding stem cells enormous opportunities
Ear inside the scall compartments and receptors responsible for hearing highly differentiated tall ask to identify cell for anticipated differentiation
The dynamics of venture/PE investing and IPOs are fast evolving. What are the drivers – will the number of investors grow will the size of early rounds continue to grow? How is this reflected in GCT target areas, company design, and biotech overall? Do patients benefit from these trends? Is crossover investing a distinct class or a little of both? Why did it emerge and what are the characteristics of the players? Will SPACs play a role in the growth of the gene and cell therapy industry. What is the role of corporate investment arms eg NVS, Bayer, GV, etc. – has a category killer emerged? Are we nearing the limit of what the GCT market can absorb or will investment capital continue to grow unabated? Moderator: Roger Kitterman
VP, Venture, Mass General Brigham
Saturation reached or more investment is coming in CGT
Pharmacologic agent in existing cause another disorders locomo-movement related
efficacy Autologous cell therapy transplantation approach program T cells into dopamine generating neurons greater than Allogeneic cell transplantation
Current market does not have delivery mechanism that a drug-delivery is the solution Trials would fail on DELIVERY
Immune suppressed patients during one year to avoid graft rejection Autologous approach of Parkinson patient genetically mutated reprogramed as dopamine generating neuron – unknowns are present
Circuitry restoration
Microenvironment disease ameliorate symptoms – education of patients on the treatment
Nearly one hundred senior Mass General Brigham Harvard faculty contributed to the creation of this group of twelve GCT technologies that they believe will breakthrough in the next two years. The Disruptive Dozen identifies and ranks the GCT technologies that will be available on at least an experimental basis to have the chance of significantly improving health care. 11:35 AM – 11:45 AM
The co-chairs convene to reflect on the insights shared over the three days. They will discuss what to expect at the in-person GCT focused May 2-4, 2022 World Medical Innovation Forum.
ALL THE TWEETS PRODUCED ON MAY 21, 2021 INCLUDE THE FOLLOWING:
Bob Carter, MD, PhD Chairman, Department of Neurosurgery, MGH William and Elizabeth Sweet, Professor of Neurosurgery, HMS Neurogeneration REVERSAL or slowing down?
Penelope Hallett, PhD NRL, McLean Assistant Professor Psychiatry, HMS efficacy Autologous cell therapy transplantation approach program T cells into dopamine genetating cells greater than Allogeneic cell transplantation
Roger Kitterman VP, Venture, Mass General Brigham Saturation reached or more investment is coming in CGT Multi OMICS and academia originated innovations are the most attractive areas
Peter Kolchinsky, PhD Founder and Managing Partner, RA Capital Management Future proof for new comers disruptors Ex Vivo gene therapy to improve funding products what tool kit belongs to
Chairman, Department of Neurosurgery, MGH, Professor of Neurosurgery, HMS Cell therapy for Parkinson to replace dopamine producing cells lost ability to produce dopamine skin cell to become autologous cells reprogramed
Kapil Bharti, PhD Senior Investigator, Ocular and Stem Cell Translational Research Section, NIH Off-th-shelf one time treatment becoming cure Intact tissue in a dish is fragile to maintain metabolism to become like semiconductors
Ole Isacson, MD, PhD Director, Neuroregeneration Research Institute, McLean Professor, Neurology and Neuroscience, MGH, HMS Opportunities in the next generation of the tactical level Welcome the oprimism and energy level of all
Erin Kimbrel, PhD Executive Director, Regenerative Medicine, Astellas In the ocular space immunogenecity regulatory communication use gene editing for immunogenecity Cas1 and Cas2 autologous cells
Nabiha Saklayen, PhD CEO and Co-Founder, Cellino scale production of autologous cells foundry using semiconductor process in building cassettes by optic physicists
Joe Burns, PhD VP, Head of Biology, Decibel Therapeutics Ear inside the scall compartments and receptors responsible for hearing highly differentiated tall ask to identify cell for anticipated differentiation control by genomics
Kapil Bharti, PhD Senior Investigator, Ocular and Stem Cell Translational Research Section, NIH first drug required to establish the process for that innovations design of animal studies not done before
Robert Nelsen Managing Director, Co-founder, ARCH Venture Partners Manufacturing change is not a new clinical trial FDA need to be presented with new rethinking for big innovations Drug pricing cheaper requires systematization
David Berry, MD, PhD CEO, Valo Health GP, Flagship Pioneering Bring disruptive frontier platform reliable delivery CGT double knockout disease cure all change efficiency scope human centric vs mice centered right scale acceleration
Kush Parmar, MD, PhD Managing Partner, 5AM Ventures build it yourself, benefit for patients FIrst Look at MGB shows MEE innovation on inner ear worthy investment
Robert Nelsen Managing Director, Co-founder, ARCH Venture Partners Frustration with supply chain during the Pandemic, GMC anticipation in advance CGT rapidly prototype rethink and invest proactive investor .edu and Pharma
Intellia announced in its fourth-quarter earnings report that Novartis had ended development of sickle cell treatment OTQ923/HIX763. (Getty Images)
Novartis will no longer develop an ex vivo sickle cell disease program that was part of an older deal with Intellia, and the gene editing biotech’s CEO John Leonard, M.D., thinks he knows why.
“We’ve always believed that the future lies with the in vivo approaches, and that’s been a focus of the work that we do,” Leonard said. “I’m sure they looked at the ex vivo space and may have had some of the same realizations that we had some years ago.”
Leonard, of course, said he wasn’t completely sure why Novartis opted to cut the program, but noted that the Big Pharma is undergoing a broad pipeline reorganization.
Novartis confirmed just that in an emailed statement to Fierce Biotech, saying that the program was discontinued for strategic reasons. The overall partnership with Intellia remains intact, however, the spokesperson said.
Intellia announced in its fourth-quarter earnings report Thursday that the Swiss pharma ended development of OTQ923/HIX763 this month.
The therapy uses autologous, ex vivo, CRISPR-edited hematopoietic stem cells to target fetal hemoglobin for treating sickle cell disease. Novartis initiated dosing on a phase 1/2 trial for the Intellia-partnered program in 2021.
Intellia has both types of candidate in its pipeline, but the in vivo list is longer and more advanced, with NTLA-2001 in transthyretin (ATTR) amyloidosis leading the pack.
Novartis and Intellia have had a cell therapy partnership since January 2015, which was three months after Intellia launched from Atlas Venture and Caribou Biosciences. The agreement was revised in 2018 to expand to ex vivo development of cell therapies using certain ocular stem cells. At that time, Intellia received a $10 million payment, but other financial details of the agreement have not been disclosed. Novartis gained the rights to opt in on one or more programs, while Intellia earned the right to use the pharma’s lipid nanoparticle technology for all genome editing applications in both in vivo and ex vivo settings.
Intellia, working with its partner Regeneron, has shown over the past year that CRISPR/Cas9 in vivo gene editing can cause high, seemingly durable levels of gene knockdown in humans. While questions about the Intellia data, and the concept more broadly, remain unanswered, there is now early evidence that the approach may be effective and, as importantly, safe. Precision is one of a clutch of companies barreling toward the clinic in the wake of Intellia, and the potential of its Arcus platform to provide greater precision and versatility than CRISPR/Cas9 and zinc finger nuclease has now attracted a suitor.
To add to its in vivo capabilities, Novartis is set to pay $50 million in cash to partner with Precision. The deal also features a $25 million equity investment priced at $2.01 per share, a 20% premium over the recent average for the stock, as well as up to $1.4 billion in milestones, research funding and royalties ranging from the mid-single-digit to low-double-digit percentages.
Alnylam Announces First-Ever FDA Approval of an RNAi Therapeutic, ONPATTRO™ (patisiran) for the Treatment of the Polyneuropathy of Hereditary Transthyretin-Mediated Amyloidosis in Adults
Important but Unseen Human Embryo Developmental Stages Mimicked in Lab
Reporter and Curator: Dr. Sudipta Saha, Ph.D.
Scientists have created embryo-like structures that mimic a crucial yet not much known stage of human development. The structures, created from stem cells and called gastruloids, are the first to form a 3D assembly that lays out how the body will take shape. The gastruloids developed rudimentary components of a heart and nervous system, but lacked the components to form a brain and other cell types that would make them capable of becoming a viable fetus.
Human embryos take a momentous leap in their third week, when the largely homogeneous ball of cells starts to differentiate and develop specific characteristics of the body parts they will become, a process known as gastrulation. During this process, the embryo elongates and lays down a body plan with a head and tail, often called the head-to-tail axis. But scientists have never seen this process live in action. That is partly because many countries have regulations that stop embryos from being grown in the laboratory for research beyond 14 days.
Over the past years, several research groups have cultured embryonic stem-cell structures that model when cells start to differentiate. The latest model developed at the University of Cambridge, UK and their collaborators in the Netherlands, Showed for the first time what happens when the blueprint for the body’s development is laid out, around 18–21 days after conception. Genetic analysis showed that the cells formed were those that would eventually go on to form muscles in the trunk, vertebrae, heart and other organs.
If everything is done properly, the cells develop into 3D structures on their own — and then spontaneously mimic the gastrulation process. Although they display certain key features of a 21-day-old embryo, the gastruloids reach that stage after just 72 hours and survive for maximum 4 days before collapsing. Scientists will probably use the model to make structures that are even more realistic representations of early development.
The model could help scientists to understand the role of genetics and environmental factors in different disorders. The artificial structures make it possible to avoid ethical concerns about doing research on human embryos. But as the structures become more advanced and life-like, there may be ethical restrictions.
Celiac Disease Breakthrough: (1) 472 genes regulated differently in organoids reflecting celiac disease than in non-celiac control organoids (2) bio-products derived from gut microorganisms can be employed to modify the epithelial response to gluten, a finding that could lead to future treatment strategies.
Reporter: Aviva Lev-Ari, PhD, RN
“These results confirm our hypothesis that genes and exposure to gluten are necessary but not sufficient, since changes in both the composition and function of the gut microbiome are also needed to switch from genetic predisposition to clinical outcome, as shown by our data,” said Alessio Fasano, HMS professor of pediatrics at Mass General, director of MIBRC and co-senior author of the paper.
Celiac disease (CD) is an immune-mediated disorder triggered by gluten exposure. The contribution of the adaptive immune response to CD pathogenesis has been extensively studied, but the absence of valid experimental models has hampered our understanding of the early steps leading to loss of gluten tolerance. Using intestinal organoids developed from duodenal biopsies from both non-celiac (NC) and celiac (CD) patients, we explored the contribution of gut epithelium to CD pathogenesis and the role of microbiota-derived molecules in modulating the epithelium’s response to gluten. When compared to NC, RNA sequencing of CD organoids revealed significantly altered expression of genes associated with gut barrier, innate immune response, and stem cell functions. Monolayers derived from CD organoids exposed to gliadin showed increased intestinal permeability and enhanced secretion of pro-inflammatory cytokines compared to NC controls. Microbiota-derived bioproducts butyrate, lactate, and polysaccharide A improved barrier function and reduced gliadin-induced cytokine secretion. We concluded that: (1) patient-derived organoids faithfully express established and newly identified molecular signatures characteristic of CD. (2) microbiota-derived bioproducts can be used to modulate the epithelial response to gluten. Finally, we validated the use of patient-derived organoids monolayers as a novel tool for the study of CD.
Mass. General researchers develop 3D “mini-gut” model to study autoimmune response to gluten in celiac and non-celiac patient tissue
Gene expression of intestinal organoids reflects functional differences found in celiac disease
In pursuit of a novel tool for the research and treatment of celiac disease, scientists at the Mucosal Immunology and Biology Research Center (MIBRC) at Massachusetts General Hospital (MGH) have validated the use of intestinal organoids. These three-dimensional tissue cultures are miniature, simplified versions of the intestine produced in vitro. Taking tissue from duodenal biopsies of celiac and non-celiac patients, researchers created the “mini-guts” to explore how the gut epithelium and microbiota-derived molecules respond to gluten, a complex class of proteins found in wheat and other grains.
“We currently have no animal model that can recapitulate the response to gluten that we see in humans,” says Stefania Senger, PhD, co-senior author of the study published in Scientific Reports this week. “Using this human tissue model, we observed that intestinal organoids express the same molecular markers as actual epithelium in the celiac tissue, and the signature gene expression reflects the functional differences that occur when epithelia of celiac disease patients are exposed to gliadin.” Gliadin and glutenin proteins are main components of gluten.
Celiac disease is triggered when genetically predisposed individuals consume gluten. The condition affects approximately 1 percent of the U.S. population. Based on current data, the onset of celiac disease is thought to be preceded by the release of the protein zonulin, which is triggered by the activation of undigested gliadin to induce an autoimmune response. This leads to increased intestinal permeability and a disrupted barrier function. Novel evidence suggests that the microorganisms in the gastrointestinal tract may play a role in the onset of celiac disease.
Earlier studies from the MIBRC group and others have shown that human organoids “retain a gene expression that recapitulates the expression of the tissue of origin, including a diseased state,” the authors write. Through RNA sequencing, the new findings validate the organoid model as a “faithful in vitro model for celiac disease,” Senger says.
Using whole-transcriptome analysis, the researchers identified 472 genes regulated differently in organoids reflecting celiac disease than in non-celiac control organoids. These included novel genes associated with epithelial functions related to the pathogenesis of celiac disease – including gut barrier maintenance, stem cell regeneration and innate immune response. A second finding of the study shows that bioproducts derived from gut microorganisms can be employed to modify the epithelial response to gluten, a finding that could lead to future treatment strategies.
“These results confirm our hypothesis that genes and exposure to gluten are necessary but not sufficient, since changes in both the composition and function of the gut microbiome are also needed to switch from genetic predisposition to clinical outcome, as shown by our data,” says Alessio Fasano, MD, director of the Mucosal Immunology and Biology Research Center and co-senior author.
Senger adds, “We believe our observations represent a major shift in the study of celiac disease. We are confident that with adequate funding we could achieve major goals that include the development and implementation of high-throughput drug screenings to quickly identify new treatments for patients and expand the organoid repository to develop more complex models and pursue personalized treatment.”
Additional co-authors of the paper are first author Rachel Freire, PhD, along with Laura Ingano and Gloria Serena, PhD, of the MGH MIBRC; Murat Cetinbas, PhD, and Ruslan Sadreyev, PhD, MGH Department of Molecular Biology; Anthony Anselmo, PhD, formerly of MGH Molecular Biology and now with PatientsLikeMe, Cambridge, Mass.; and Anna Sapone, MD, PhD, Takeda Pharmaceuticals International. Support for the study includes National Institutes of Health grants RO1 DK104344-01A1 and 1U19 AI082655-02 and the Egan Family Foundation.
Extracellular RNA and their carriers in disease diagnosis and therapy, Volume 2 (Volume Two: Latest in Genomics Methodologies for Therapeutics: Gene Editing, NGS and BioInformatics, Simulations and the Genome Ontology), Part 1: Next Generation Sequencing (NGS)
Reporter and Curator: Dr. Sudipta Saha, Ph.D.
RNA plays various roles in determining how the information in our genes drives cell behavior. One of its roles is to carry information encoded by our genes from the cell nucleus to the rest of the cell where it can be acted on by other cell components. Rresearchers have now defined how RNA also participates in transmitting information outside cells, known as extracellular RNA or exRNA. This new role of RNA in cell-to-cell communication has led to new discoveries of potential disease biomarkers and therapeutic targets. Cells using RNA to talk to each other is a significant shift in the general thought process about RNA biology.
Researchers explored basic exRNA biology, including how exRNA molecules and their transport packages (or carriers) were made, how they were expelled by producer cells and taken up by target cells, and what the exRNA molecules did when they got to their destination. They encountered surprising complexity both in the types of carriers that transport exRNA molecules between cells and in the different types of exRNA molecules associated with the carriers. The researchers had to be exceptionally creative in developing molecular and data-centric tools to begin making sense of the complexity, and found that the type of carrier affected how exRNA messages were sent and received.
As couriers of information between cells, exRNA molecules and their carriers give researchers an opportunity to intercept exRNA messages to see if they are associated with disease. If scientists could change or engineer designer exRNA messages, it may be a new way to treat disease. The researchers identified potential exRNA biomarkers for nearly 30 diseases including cardiovascular disease, diseases of the brain and central nervous system, pregnancy complications, glaucoma, diabetes, autoimmune diseases and multiple types of cancer.
As for example some researchers found that exRNA in urine showed promise as a biomarker of muscular dystrophy where current studies rely on markers obtained through painful muscle biopsies. Some other researchers laid the groundwork for exRNA as therapeutics with preliminary studies demonstrating how researchers might load exRNA molecules into suitable carriers and target carriers to intended recipient cells, and determining whether engineered carriers could have adverse side effects. Scientists engineered carriers with designer RNA messages to target lab-grown breast cancer cells displaying a certain protein on their surface. In an animal model of breast cancer with the cell surface protein, the researchers showed a reduction in tumor growth after engineered carriers deposited their RNA cargo.
Other than the above research work the scientists also created a catalog of exRNA molecules found in human biofluids like plasma, saliva and urine. They analyzed over 50,000 samples from over 2000 donors, generating exRNA profiles for 13 biofluids. This included over 1000 exRNA profiles from healthy volunteers. The researchers found that exRNA profiles varied greatly among healthy individuals depending on characteristics like age and environmental factors like exercise. This means that exRNA profiles can give important and detailed information about health and disease, but careful comparisons need to be made with exRNA data generated from people with similar characteristics.
Next the researchers will develop tools to efficiently and reproducibly isolate, identify and analyze different carrier types and their exRNA cargos and allow analysis of one carrier and its cargo at a time. These tools will be shared with the research community to fill gaps in knowledge generated till now and to continue to move this field forward.
Ido Sagi – PhD Student @HUJI, 2017 Kaye Innovation Award winner for leading research that yielded the first successful isolation and maintenance of haploid embryonic stem cells in humans.
Reporter: Aviva Lev-Ari, PhD, RN
Ido Sagi – PhD Student, Silberman Institute of Life Sciences, HUJI, Israel
Ido Sagi’s research focuses on studying genetic and epigenetic phenomena in human pluripotent stem cells, and his work has been published in leading scientific journals, including Nature, Nature Genetics and Cell Stem Cell.
Ido Sagi received BSc summa cum laude in Life Sciences from the Hebrew University, and currently pursues a PhD at the laboratory of Prof. Nissim Benvenisty at the university’s Department of Genetics in the Alexander Silberman Institute of Life Sciences.
2017 Kaye Innovation Award winner for leading research that yielded the first successful isolation and maintenance of haploid embryonic stem cells in humans.
The Kaye Innovation Awards at the Hebrew University of Jerusalem have been awarded annually since 1994. Isaac Kaye of England, a prominent industrialist in the pharmaceutical industry, established the awards to encourage faculty, staff and students of the Hebrew University to develop innovative methods and inventions with good commercial potential, which will benefit the university and society.
Hebrew University of Jerusalem’s Azrieli Center for Stem Cells and Genetic Research, led research that yielded the first successful isolation and maintenance of haploid embryonic stem cells in humans.
Together with Prof. Nissim Benvenisty, Director of the Azrieli Center, Sagi showed that this new human stem cell type will play an important role in human genetic and medical research. It will aid our understanding of human development – for example, why we reproduce sexually instead of from a single parent. It will make genetic screening easier and more precise, by allowing the examination of single sets of chromosomes. And it is already enabling the study of resistance to chemotherapy drugs, with implications for cancer therapy.
Read more at https://www.breakingisraelnews.com/90561/hebrew-u-isolates-haploid-human-stem-cells-changing-future-of-medicine/#impRGtg0syOSFGtZ.99
He is a fellow of the Adams Fellowship of the Israel Academy of Sciences and Humanities, and
Has recently received the Rappaport Prize for Excellence in Biomedical Research.
The Azrieli Center for Stem Cells and Genetic Research, Department of Genetics, Silberman Institute of Life Sciences, The Hebrew University, Jerusalem 91904, Israel. Electronic address:
Nat Protoc 2016 Nov 20;11(11):2274-2286. Epub 2016 Oct 20.
The Azrieli Center for Stem Cells and Genetic Research, Department of Genetics, Silberman Institute of Life Sciences, The Hebrew University, Jerusalem, Israel.
The Azrieli Center for Stem Cells and Genetic Research, Department of Genetics, Silberman Institute of Life Sciences, The Hebrew University, Jerusalem 91904, Israel. Electronic address:
Nature 2016 Apr 16;532(7597):107-11. Epub 2016 Mar 16.
The Azrieli Center for Stem Cells and Genetic Research, Department of Genetics, Silberman Institute of Life Sciences, The Hebrew University, Jerusalem 91904, Israel.
Nat Rev Mol Cell Biol 2016 Mar 28;17(3):170-82. Epub 2016 Jan 28.
The Azrieli Center for Stem Cells and Genetic Research, Institute of Life Sciences, Hebrew University of Jerusalem, Givat-Ram, Jerusalem 91904, Israel.
Cell Stem Cell 2014 Nov 6;15(5):634-42. Epub 2014 Nov 6.
The New York Stem Cell Foundation Research Institute, New York, NY 10032, USA; Naomi Berrie Diabetes Center & Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA. Electronic address:
Nature 2016 12 30;540(7632):211-212. Epub 2016 Nov 30.
The Azrieli Center for Stem Cells and Genetic Research, Department of Genetics, Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel.
Other related articles on Genetic and Epigenetic phenomena in human pluripotent stem cells published by LPBI Group can be found in the following e-Books on Amazon.com
2.1.5.5 Promising research for a male birth control pill, Volume 2 (Volume Two: Latest in Genomics Methodologies for Therapeutics: Gene Editing, NGS and BioInformatics, Simulations and the Genome Ontology), Part 2: CRISPR for Gene Editing and DNA Repair
Scientists think excessive population growth is a cause of scarcity and environmental degradation. A male pill could reduce the number of unintended pregnancies, which accounts for 40 percent of all pregnancies worldwide.
But, big drug companies long ago dropped out of the search for a male contraceptive pill which is able to chemically intercept millions of sperm before they reach a woman’s egg. Right now the chemical burden for contraception relies solely on the female. There’s not much activity in the male contraception field because an effective solution is available on the female side.
Presently, male contraception means a condom or a vasectomy. But researchers from Center for Drug Discovery at Baylor College of Medicine, USA are renewing the search for a better option—an easy-to-take pill that’s safe, fast-acting, and reversible.
The scientists began with lists of genes active in the testes for sperm production and motility and then created knockout mice that lack those genes. Using the gene-editing technology called CRISPR, in collaboration with Japanese scientists, they have so far made more than 75 of these “knockout” mice.
They allowed these mice to mate with normal (wild type) female mice, and if their female partners don’t get pregnant after three to six months, it means the gene might be a target for a contraceptive. Out of 2300 genes that are particularly active in the testes of mice, the researchers have identified 30 genes whose deletion makes the male infertile. Next the scientists are planning a novel screening approach to test whether any of about two billion chemicals can disable these genes in a test tube. Promising chemicals could then be fed to male mice to see if they cause infertility.
Female birth control pills use hormones to inhibit a woman’s ovaries from releasing eggs. But hormones have side effects like weight gain, mood changes, and headaches. A trial of one male contraceptive hormone was stopped early in 2011 after one participant committed suicide and others reported depression. Moreover, some drug candidates have made animals permanently sterile which is not the goal of the research. The challenge is to prevent sperm being made without permanently sterilizing the individual.
As a better way to test drugs, Scientists at University of Georgia, USA are investigating yet another high-tech approach. They are turning human skin cells into stem cells that look and act like the spermatogonial cells in the testes. Testing drugs on such cells might provide more accurate leads than tests on mice.
The male pill would also have to start working quickly, a lot sooner than the female pill, which takes about a week to function. Scientists from University of Dundee, U.K. admitted that there are lots of challenges. Because, a women’s ovary usually release one mature egg each month, while a man makes millions of sperm every day. So, the male pill has to be made 100 percent effective and act instantaneously.
Translation of whole human genome sequencing to clinical practice: The Joint Initiative for Metrology in Biology (JIMB) is a collaboration between the National Institute of Standards & Technology (NIST) and Stanford University, Volume 2 (Volume Two: Latest in Genomics Methodologies for Therapeutics: Gene Editing, NGS and BioInformatics, Simulations and the Genome Ontology), Part 1: Next Generation Sequencing (NGS)
Translation of whole human genome sequencing to clinical practice: The Joint Initiative for Metrology in Biology (JIMB) is a collaboration between the National Institute of Standards & Technology (NIST) and Stanford University.
Reporter: Aviva Lev-Ari, PhD, RN
JIMB’s mission is to advance the science of measuring biology (biometrology). JIMB is pursuing fundamental research, standards development, and the translation of products that support confidence in biological measurements and reliable reuse of materials and results. JIMB is particularly focused on measurements and technologies that impact, are related to, or enabled by ongoing advances in and associated with the reading and writing of DNA.
Stanford innovators and industry entrepreneurs have joined forces with the measurement experts from NIST to create a new engine powering the bioeconomy. It’s called JIMB — “Jim Bee” — the Joint Initiative for Metrology in Biology. JIMB unites people, platforms, and projects to underpin standards-based research and innovation in biometrology.
Genome in a Bottle
Authoritative Characterization of
Benchmark Human Genomes
The Genome in a Bottle Consortium is a public-private-academic consortium hosted by NIST to develop the technical infrastructure (reference standards, reference methods, and reference data) to enable translation of whole human genome sequencing to clinical practice. The priority of GIAB is authoritative characterization of human genomes for use in analytical validation and technology development, optimization, and demonstration. In 2015, NIST released the pilot genome Reference Material 8398, which is genomic DNA (NA12878) derived from a large batch of the Coriell cell line GM12878, characterized for high-confidence SNPs, indel, and homozygous reference regions (Zook, et al., Nature Biotechnology 2014).
There are four new GIAB reference materials available. With the addition of these new reference materials (RMs) to a growing collection of “measuring sticks” for gene sequencing, we can now provide laboratories with even more capability to accurately “map” DNA for genetic testing, medical diagnoses and future customized drug therapies. The new tools feature sequenced genes from individuals in two genetically diverse groups, Asians and Ashkenazic Jews; a father-mother-child trio set from Ashkenazic Jews; and four microbes commonly used in research. For more informationclick here. To purchase them, visit:
Data and analyses are publicly available (GIAB GitHub). A description of data generated by GIAB is published here. To standardize best practices for using GIAB genomes for benchmarking, we are working with the Global Alliance for Genomics and Health Benchmarking Team (benchmarking tools).
High-confidence small variant and homozygous reference calls are available for NA12878, the Ashkenazim trio, and the Chinese son with respect to GRCh37. Preliminary high-confidence calls with respect to GRCh38 are also available for NA12878. The latest version of these calls is under the latest directory for each genome on the GIAB FTP.
The consortium was initiated in a set of meetings in 2011 and 2012, and the consortium holds open, public workshops in January at Stanford University in Palo Alto, CA and in August/September at NIST in Gaithersburg, MD. Slides from workshops and conferences are available online. The consortium is open and welcomes new participants.
Stanford innovators and industry entrepreneurs have joined forces with the measurement experts from NIST to create a new engine powering the bioeconomy. It’s called JIMB — “Jim Bee” — the Joint Initiative for Metrology in Biology. JIMB unites people, platforms, and projects to underpin standards-based research and innovation in biometrology.
JIMB’s mission is to motivate standards-based measurement innovation to facilitate translation of basic science and technology development breakthroughs in genomics and synthetic biology.
By advancing biometrology, JIMB will push the boundaries of discovery science, accelerate technology development and dissemination, and generate reusable resources.
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