Oligonucleotide therapeutics: challenges and opportunities

Dr C. Frank Bennett, Chief Scientific Officer, Ionis Pharmaceuticals, Carlsbad, CA USA

Dr. Bennett is the chief scientific officer at Ionis Pharmaceuticals and one of the founding members of the company. Dr. Bennett is a co-recipient of the 2019 Breakthrough Prize in Life Sciences and the 2021 Gabbay Award for his contributions to the discovery and development of SPINRAZA® (nusinersen), the 2018 Hereditary Disease Foundation's (HDF) Leslie Gehry Brenner Prize for Innovation in Science for his leadership and continued commitment to developing antisense therapies for Huntington's disease (HD). Dr. Bennett has published more than 250 papers in the field of antisense research and development, and he is an inventor on more than 175 issued U.S. patents. He received his Ph.D. in Pharmacology from Baylor College of Medicine, Houston, Texas and his B.S. degree in Pharmacy from the University of New Mexico, Albuquerque, New Mexico. 

Professor Anastasia Khvorova, University of Massachusetts Medical School

Anastasia Khvorova, PhD, is The Remondi Family Chair in Biomedical Research and Professor in the RNA Therapeutics Institute (RTI) and Program in Molecular Medicine at the University of Massachusetts Medical School (UMMS). She has more than twenty years of experience developing oligonucleotide technology and therapeutics. Her lab brings together hardcore organic and oligonucleotide chemists, RNA biologists, and pharmacologists to develop novel approaches and solutions to understanding natural and therapeutic RNA trafficking and delivery. She established the RTI’s Nucleic Acid Chemistry Center, which provides expertise in RNA chemistry to labs within and outside UMMS, and is the only non-profit center in North America capable of synthesizing complex RNAs at scales necessary to support both in vitro and in vivo studies. Dr Khvorova joined UMMS after several years in industry, during which she served as Chief Scientific Officer at lead biotech companies (Dharmacon, ThermoFisher; RXi Pharmaceuticals). She is At-Large Director and Scientific & Research Council Chair of the American Society of Gene & Cell Therapy and served for several years as Director of the Oligonucleotide Therapeutics Society. Dr Khvorova is named as inventor on more than 150 patents and 200 patent applications, and she has authored more than 80 peer-reviewed publications, including seminal articles in Cell, Nature, and Nature Biotechnology (citation index exceeding 2000 per article) defining the field of RNAi drug design and development. Dr Khvorova is principal investigator on four major National Institutes of Health grants.

Professor Matthew Wood, University of Oxford

Matthew Wood FMedSci is Professor of Neuroscience and Deputy Head of the Medical Sciences Division at the University of Oxford. He directs the Laboratory of RNA biology and Neuromuscular Disease investigating development of RNA-based medicines for neuromuscular disease focusing on the development of advanced generation antisense oligonucleotides for Duchenne muscular dystrophy and related neuromuscular conditions. He is currently Director of MDUK Oxford Neuromuscular Centre and Director of the Oxford Harrington Rare Disease Centre. He has pioneered the development of novel drug delivery systems including peptide and exosome-based technologies for RNA delivery. He is a co-founder of the biotech spin-outs Evox Therapeutics and PepGen, and has recently led a major UK national initiative to establish a UK Nucleic Acid Therapy Accelerator (NATA). Matthew is or has been an advisor to numerous research funding agencies including the UK Medical Research Council and Wellcome Trust. 

Dr C. Frank Bennett, Chief Scientific Officer, Ionis Pharmaceuticals, Carlsbad, CA USA

Dr. Bennett is the chief scientific officer at Ionis Pharmaceuticals and one of the founding members of the company. Dr. Bennett is a co-recipient of the 2019 Breakthrough Prize in Life Sciences and the 2021 Gabbay Award for his contributions to the discovery and development of SPINRAZA® (nusinersen), the 2018 Hereditary Disease Foundation's (HDF) Leslie Gehry Brenner Prize for Innovation in Science for his leadership and continued commitment to developing antisense therapies for Huntington's disease (HD). Dr. Bennett has published more than 250 papers in the field of antisense research and development, and he is an inventor on more than 175 issued U.S. patents. He received his Ph.D. in Pharmacology from Baylor College of Medicine, Houston, Texas and his B.S. degree in Pharmacy from the University of New Mexico, Albuquerque, New Mexico. 

Professor Anastasia Khvorova, University of Massachusetts Medical School

Anastasia Khvorova, PhD, is The Remondi Family Chair in Biomedical Research and Professor in the RNA Therapeutics Institute (RTI) and Program in Molecular Medicine at the University of Massachusetts Medical School (UMMS). She has more than twenty years of experience developing oligonucleotide technology and therapeutics. Her lab brings together hardcore organic and oligonucleotide chemists, RNA biologists, and pharmacologists to develop novel approaches and solutions to understanding natural and therapeutic RNA trafficking and delivery. She established the RTI’s Nucleic Acid Chemistry Center, which provides expertise in RNA chemistry to labs within and outside UMMS, and is the only non-profit center in North America capable of synthesizing complex RNAs at scales necessary to support both in vitro and in vivo studies. Dr Khvorova joined UMMS after several years in industry, during which she served as Chief Scientific Officer at lead biotech companies (Dharmacon, ThermoFisher; RXi Pharmaceuticals). She is At-Large Director and Scientific & Research Council Chair of the American Society of Gene & Cell Therapy and served for several years as Director of the Oligonucleotide Therapeutics Society. Dr Khvorova is named as inventor on more than 150 patents and 200 patent applications, and she has authored more than 80 peer-reviewed publications, including seminal articles in Cell, Nature, and Nature Biotechnology (citation index exceeding 2000 per article) defining the field of RNAi drug design and development. Dr Khvorova is principal investigator on four major National Institutes of Health grants.

Professor Matthew Wood, University of Oxford

Matthew Wood FMedSci is Professor of Neuroscience and Deputy Head of the Medical Sciences Division at the University of Oxford. He directs the Laboratory of RNA biology and Neuromuscular Disease investigating development of RNA-based medicines for neuromuscular disease focusing on the development of advanced generation antisense oligonucleotides for Duchenne muscular dystrophy and related neuromuscular conditions. He is currently Director of MDUK Oxford Neuromuscular Centre and Director of the Oxford Harrington Rare Disease Centre. He has pioneered the development of novel drug delivery systems including peptide and exosome-based technologies for RNA delivery. He is a co-founder of the biotech spin-outs Evox Therapeutics and PepGen, and has recently led a major UK national initiative to establish a UK Nucleic Acid Therapy Accelerator (NATA). Matthew is or has been an advisor to numerous research funding agencies including the UK Medical Research Council and Wellcome Trust. 

Dr Ritwick Sawarkar, MRC Investigator, MRC Toxicology Unit, University of Cambridge.

Ritwick studied Microbiology and Biochemistry in Mumbai (India) and obtained his PhD in 2010 from Indian Institute of Science, Bangalore. Ritwick then moved to the Department of Biosystems Science and Engineering of ETH-Zürich in Basel (Switzerland) as a postdoctoral fellow with Renato Paro. In 2014, Ritwick started his own independent group at the Max Planck Institute of Immunobiology and Epigenetics in Freiburg (Germany), before moving to the MRC Toxicology Unit in 2019. Ritwick received the ERC Consolidator Grant in 2018 and Alfred Tissières Young Investigator Award in 2019.

Dr Muthiah Manoharan, Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA

Dr Muthiah (Mano) Manoharan serves as  a Senior Vice President of Drug Innovation, a Scientific Advisory Board Member, and a Distinguished Research Scientist at Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA. In 2003, he was the founding chemist hired at Alnylam as the Head of the Drug Discovery. He and his team pioneered the discovery and development of the chemical modifications, GalNAc conjugation chemistry, and LNP delivery platform that make RNA interference-based human therapeutics possible. This work led to the approval of four RNAi therapeutics: ONPATTRO® (patisiran, 2018),  GIVLAARI® (givosiran, 2019), OXLUMO® (lumasiran, 2020) and Lequio® (inclisiran, 2020, 2021). 

Dr Manoharan has had a distinguished career as a world-leading chemist in the field of oligonucleotides. He is an author of more than 230 publications (nearly 53,000 Google Scholar citations with an h-index of 105 and an i10-index of 405) and over 500 abstracts, as well as an inventor of over 250 issued US patents. Prior to Alnylam, Dr Manoharan worked in the field of antisense oligonucleotide therapeutics at Ionis (formerly Isis) Pharmaceuticals and LifeCodes Corporation (1988-1990) . 

Dr Manoharan received his B.Sc. and M.Sc. degrees in chemistry at the American College, Madurai, Tamil Nādu, India. He earned his PhD in chemistry (with Professor Ernest L. Eliel) at the University of North Carolina, Chapel Hill and carried out post-doctoral research (with Professor John A.Gerlt) in the field of oligonucleotide chemistry at Yale University and at the University of Maryland. Dr Manoharan is the winner of the Lifetime Achievement Award of the Oligonucleotide Therapeutics Society (2019),  the M. L. Wolfrom Award (2007) and D. Horton Industrial Carbohydrate Chemistry Award from the American Chemical Society (2021).

Professor Nick Lench, Executive Director, NATA

Nick is a co-founder of Congenica Limited, a genomic medicine and digital health company based at the Wellcome Genome Campus, Cambridge and held positions of COO and CSO prior to his appointment at NATA. Nick has worked in academia, industry and the NHS and has extensive experience in personalised medicine and clinical diagnostics. Prior to Congenica, Nick was Director of the NE Thames Regional Genetics Service at Great Ormond Street Hospital for Children, London. Nick was awarded a personal chair in Medical Genetics at Cardiff University, is currently an honorary reader in Genetics and Genomic Medicine at UCL and a fellow of the Royal College of Pathologists. 

Dr David R Jones

On leaving University with a BSc in Biochemistry, David joined the Huntingdon Research Centre in 1978 and spent 8 years in Contract Toxicology before moving to Fisons Pharmaceuticals, where he spent 11 years as a Toxicologist.  In 1996, David joined the UK’s Medicines Control Agency (MCA), which subsequently became the Medicines and Healthcare products Regulatory Agency (MHRA), where he was an Expert PharmacoToxicologist.  David retired at the end of 2021 and now work as a consultant.

David's primary role at MHRA principally involved assessing nonclinical data for Clinical Trial Authorisation (CTAs) Applications, both non-biological and biological.  A further aspect of his job was to offer regulatory and scientific advice to companies.  While the UK was part of the EU, he was the UK representative on the EU’s Safety Working Party (SWP). He represented the EU at ICH on the revision of the M3 Guideline and on the ICH S10 and S11 Guidelines.

David is a Fellow of the British Toxicology Society and a Fellow of the Royal Society of Biology.

David is a guest lecturer at a number of universities and a frequent presenter at conferences around the world.  He has also authored and co-authored numerous papers in various Toxicology journals.

Dr Steve Hood, GSK

Steve is a Senior Research Director at GSK having joined Glaxo Group research in 1993 with a PhD in Molecular toxicology. Following the formation of GSK in 2001, Steve managed a team determining the drug-drug interaction liabilities while developing ADME strategies for the emerging GSK antibody portfolio. In 2010, Steve led a cross divisional team focusing on the delivery issues inherent in GSK’s diverse oligonucleotide portfolio. In 2011 Steve initiated the active IMI academic/Industry COMPACT collaboration and he is actively involved in facilitating the interaction between academia , biotech and large industry partners.

Steve’s current role is the Director of Imaging Networks at GSK and is responsible for the academic Bioimaging Expertise Network (BEN). Steve ensures that academic collaborators are connected through common goals to address the gaps in GSK’s Bioimaging capability.

Steve holds Fellowships with the Royal Society of Biology, the DMDG and the GSK Fellows Community.

Dr Muthiah Manoharan, Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA

Dr Muthiah (Mano) Manoharan serves as  a Senior Vice President of Drug Innovation, a Scientific Advisory Board Member, and a Distinguished Research Scientist at Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA. In 2003, he was the founding chemist hired at Alnylam as the Head of the Drug Discovery. He and his team pioneered the discovery and development of the chemical modifications, GalNAc conjugation chemistry, and LNP delivery platform that make RNA interference-based human therapeutics possible. This work led to the approval of four RNAi therapeutics: ONPATTRO® (patisiran, 2018),  GIVLAARI® (givosiran, 2019), OXLUMO® (lumasiran, 2020) and Lequio® (inclisiran, 2020, 2021). 

Dr Manoharan has had a distinguished career as a world-leading chemist in the field of oligonucleotides. He is an author of more than 230 publications (nearly 53,000 Google Scholar citations with an h-index of 105 and an i10-index of 405) and over 500 abstracts, as well as an inventor of over 250 issued US patents. Prior to Alnylam, Dr Manoharan worked in the field of antisense oligonucleotide therapeutics at Ionis (formerly Isis) Pharmaceuticals and LifeCodes Corporation (1988-1990) . 

Dr Manoharan received his B.Sc. and M.Sc. degrees in chemistry at the American College, Madurai, Tamil Nādu, India. He earned his PhD in chemistry (with Professor Ernest L. Eliel) at the University of North Carolina, Chapel Hill and carried out post-doctoral research (with Professor John A.Gerlt) in the field of oligonucleotide chemistry at Yale University and at the University of Maryland. Dr Manoharan is the winner of the Lifetime Achievement Award of the Oligonucleotide Therapeutics Society (2019),  the M. L. Wolfrom Award (2007) and D. Horton Industrial Carbohydrate Chemistry Award from the American Chemical Society (2021).

Dr Annemieke Aartsma-Rus, Professor of translational genetics, Department of Human Genetics, Leiden University Medical Center

Professor Dr Annemieke Aartsma-Rus is a professor of Translational Genetics at the Department of Human Genetics of the Leiden University Medical Center. She played an important role in the development of antisense mediated exon skipping for Duchenne muscular dystrophy during her PhD research (2000-2004) at the Leiden University Medical Center (the Netherlands). In 2020 she co-founded the Dutch Center for RNA Therapeutics (DCRT), a non-for-profit academic collaboration aiming to develop clinical treatment with exon skipping therapies for eligible patients with unique mutations.

She has published over 210 peer-reviewed papers, 11 book chapters, 15 patents. She has given many invited lectures at scientific conferences and patient organization meetings. She was President of the Oligonucleotide Therapeutics Society from 2019-2021. She has been selected as most influential scientist in Duchenne muscular dystrophy in the past 10 years by Expertscape based on contributions to understanding and treatment of Duchenne muscular dystrophy annually since 2015.