Craig Mello, Ph. D.
Professor, UMass Medical School, USA
Nobel Prize in Physiology or Medicine (2006)
Dr. Mello’s lab uses the nematode C. elegans as a model system to study embryogenesis and gene silencing. His collaborative work with Dr. Andrew Fire led to the discovery of RNA interference (RNAi), for which they shared the 2006 Nobel Prize in Physiology or Medicine. Together they showed that when C. elegans is exposed to double-stranded ribonucleic acid (dsRNA), a molecule that mimics a signature of viral infection, the worm mounts a sequence-specific silencing reaction that interferes with the expression of cognate cellular RNAs. Using readily produced short synthetic dsRNAs, researchers can now silence any gene inorganisms as diverse as rice and humans. RNAi allows researchers to rapidly “knock out” the expression of specific genes and, thus, to define thebiological functions of those genes. RNAi also provides a potential therapeutic avenue to silence genes that cause or contribute to diseases.Dr. Mello received his BS degree in Biochemistry from Brown University in 1982, and PhD from Harvard University in 1990. From 1990 to 1994, he conducted postdoctoral research at the Fred Hutchinson Cancer Research Center in Seattle, WA. Now Dr. Mello is an Investigator of the Howard Hughes Medical Institute, the Blais University Chair in Molecular Medicine and Co-director of the RNA Therapeutics Institute at the University of Massachusetts Medical School.Besides the Nobel Prize, Dr. Mello’s work was recognized with numerous awards and honors, including the National Academy of Sciences Molecular Biology Award (2003), the Wiley Prize in Biomedical Sciences from Rockefeller University (2003), Brandeis University’s Lewis S. Rosnstiel Award for Distinguished Work in Medical Research (2005), the Gairdner Foundation International Award (2005), the Massry Prize (2005), the Paul Ehrlich and Ludwig Darmstaedter Award (2006), the Dr. Paul Janssen Award for Biomedical Research (2006), the Hope Funds Award of Excellence in Basic Research (2008). He is a member of the National Academy of Sciences, the American Academy of Arts and Sciences, and the American Philosophical Society.
Argonaute systems interpret cues from mRNA splicing during transcriptome surveillance in Caenorhabditis elegans
In animals Argonaute small-RNA pathways scan germline transcripts to silence self-replicating genetic elements. Little is known however about how endogenous gene expression is recognized and licensed. Here we show that the presence of introns and by inference the process of mRNA splicing prevents default recognition by an Argonaute-mediated silencing mechanism in the C. elegans germline. Silencing on intronless mRNAs is initiated independently of the piRNA pathway but nevertheless employs RNA-dependent RNA polymerases (RdRPs) whose small antisense-RNA products engage Worm AGO, WAGO, Argonautes. WAGOs in turn can transitively silence cognate intron-containing reporter genes. Interestingly, although mutations that disarm the WAGO pathway prevent transitive silencing, they do not de-silence the intronless mRNA itself, indicating the existence of a second cis-acting mode of silencing that acts on intronless mRNAs. Our findings suggest that Argonaute small-RNA systems interpret cues put in place during mRNA splicing to regulate and license germline gene expression.
Oded Rechav, Ph. D.
Professor, Department of Neurobiology, Wise Faculty of Life Sciences & Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel
Prof. Oded Rechavi’s mission is to challenge fundamental long-held scientific dogmas. He found an exception to the original “Cell Theory”, provided direct evidence that an acquired trait can be inherited in nematodes, worked to elucidate an alternative transgenerational inheritance mechanism (that depends on inherited small RNA molecules, not DNA molecules), discovered a mechanism that allows nematodes’ brains to control the behavior of their progeny, utilized genome sequencing of ancient DNA to “piece together” fragments of the Dead Sea Scrolls, discovered a neuronal circuit-level mechanism that explains economic irrationality, and demonstrated that parasites can be genetically engineered to deliver drugs to the nervous system. Prof. Rechavi is an ERC Fellow, and was awarded many prestigious prizes, including the Polymath prize (Schmidt Futures), the Kadar award, the Blavatnik award, the Krill Wolf award, the Alon, and F.I.R.S.T (Bikura) Prizes, and the Gross Lipper Fellowship. Prof. Rechavi was selected as one of the “10 Most Creative People in Israel Under 40”, and one of the “40 Most Promising People in Israel Under 40”.
C.elegans Parental Experiences Regulate a Critical Decision Made by the Progeny
C. elegans can transmit certain responses transgenerationally, however it is unknown whether these can impact the process of evolution. Here, by studying nematodes that choose whether to self-reproduce or outcross, we show that inherited small RNAs affect sexual attraction and mating for multiple generations and thus indirectly control genetic variation. We found that manipulating endogenous small RNA levels in hermaphrodites induces premature secretion of a male-attracting pheromone, increases the prevalence of males, and ultimately elevates the rate of successful mating. Further, stress leads to enhanced sexual attraction which transmits transgenerationally for three generations. Simulations and multigenerational competition experiments demonstrate that the rise in mating, driven by heritable small RNAs that promote sexual attraction, can increase alleles frequencies in the population. This non-DNA based inheritance process could be a mechanism for elevating the rate of outcrossing in challenging environments, when increasing genetic variation is advantageous.
Xiang-Dong Fu, Ph. D.
Distinguished Professor, Department of Cellular and Molecular Medicine, University of California, San Diego, USA
In the early 1990s, Dr. Fu co-discovered and provided initial characterization of SR proteins from mammals, a family of conserved RNA-binding proteins involved in various aspects of mRNA production and function, including pre-mRNA splicing, mRNA export, nonsense-mediated decay and translation. His lab was then the first to identify a family of kinases specific for SR proteins, and demonstrated that these kinases are critical for transducing external and intracellular signals to regulate alternative pre-mRNA splicing in the nucleus. More recently, the research scope of Dr. Fu’s group has been expanded to understanding the mechanistic coupling between transcription and splicing, the nuclear architectural basis for regulated gene expression, and the genomics of RNA binding proteins.
Dr. Fu received his M.S. degree in Virology from Wuhan University, China in 1982, Ph.D. degree in Biochemistry from Case Western Reserve University in 1988 and post-doctoral training with Prof. Tom Maniatis at Harvard from 1988 to 1992. In 1992, Dr. Fu joined the faculty of University of California San Diego, where he currently is a Professor of Cellular and Molecular Medicine at the Institute of Genomic Medicine.
Dr. Fu’s scientific achievements have been recognized by selection for the Searle Scholar Award in 1994 and the Leukemia and Lymphoma Society Scholar Award in 1997. In 2010, he was elected a Fellow of the American Association for the Advancement of Science (AAAS)
RNA Biology leads the Way in Making New Neurons to Replenish Lost Ones in Neurodegenerative Disease
Studying the mechanisms for regulated RNA processing, we have systematically pursued an unexpected observation that depletion of a single RNA binding protein called PTB efficiently converts many different cell types into functional neurons. This establishes a new general “subtraction” strategy to trans-differentiate non-neuronal cells into neurons, which is in contrast to the commonly used “addition” approach for switching cell fate by overexpressing lineage-specific transcription factors. We have now further explored this new strategy directly in brain by converting astrocytes into functional neurons and demonstrated the reconstitution of the lost nigrostriatal pathway in a Parkinson’s disease model, which leads to potent reversal of the disease phenotype. During this investigation, we also note that astrocytes from different brain regions appear to preferentially give rise to distinct neuronal subtypes similar to endogenous neuronal populations. These findings highlight the potential applicability of the new cell replacement strategy in treating different forms of neurodegenerative diseases.
Muthiah Manoharan, Ph. D.
Senior Vice-President, Alnylam Pharmaceuticals, USA
Dr. Muthiah (Mano) Manoharan serves as a Senior Vice President, Scientific Advisory Board Member, and a Distinguished Research Scientist at Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA. In 2003, he was the first chemist hired at Alnylam. He and his team pioneered the discovery and development of the chemical modifications that make RNA interference-based human therapeutics possible. This work led to ONPATTRO (Patisiran), the first RNAi therapeutic approved by FDA in 2018. Dr. Manoharan has had a distinguished career as a world-leading chemist in the areas of oligonucleotide chemical modifications, conjugation chemistry, and delivery platforms (lipid nanoparticles, polymer conjugates, and complex-forming strategies). Dr. Manoharan and his research group demonstrated for the first time the human therapeutic applications of GalNAc-conjugated oligonucleotides at Alnylam, a platform that has revolutionized the nucleic acid-based therapeutics field with several compounds in the advanced clinical trials. He is an author of more than 215 publications (nearly 43,000 citations with an h-index of 94 and an i10-index of 367) and over 400 abstracts, as well as an inventor of over 225 issued U.S. patents. Prior to Alnylam, Dr. Manoharan worked at Ionis (formerly Isis) Pharmaceuticals and Lifecodes Corporation in the field of antisense oligonucleotide therapeutics. He received the M. L. Wolfrom Award from the American Chemical Society Carbohydrate Chemistry Division in 2007 for his contributions to this field. He has been recognized as the Lifetime Achievement Awardee of the Oligonucleotide Therapeutics Society for the year 2019.
Living in the World of RNAi Therapeutics
Small interfering RNAs (siRNAs) are a new class of novel medicine. siRNAs are potent inhibitors of gene expression; and act through the natural RNA interference (RNAi) pathway. For the discovery of this novel biological process, Fire and Mello were awarded the 2006 Nobel Prize in Physiology or Medicine. Although much hope and speculation regarding the therapeutic potential of RNAi began soon after the discovery of the pathway (Alnylam was founded in 2002), there have been challenges in realizing this potential, most related to difficulties in efficient delivery into the cells of specific organs or tissues. Our laboratory demonstrated the very first in vivo RNAi mediated silencing in mouse liver and jejunum in 2004. To deliver therapeutic siRNAs into liver hepatocytes, we have further developed a three-pronged “biomimetic” approach with the goals of enabling delivery to hepatocytes after both intravenous and subcutaneous administration. These methods include chemical modification of siRNAs, lipid nanoparticle (LNP) formulation of siRNAs, and multivalent N-acetylgalactosamine (GalNAc, a carbohydrate) conjugation of siRNAs. The LNP strategy with a partially chemically modified siRNA resulted in the first RNAi therapeutic approved by the US FDA in 2018 and it is now approved for use in Europe, Canada, and Japan. This drug, ONPATTRO®, is used to treat polyneuropathy in patients with hereditary ATTR amyloidosis. The approval of ONPATTRO® paves the way for a whole new class of RNA-based medicines. Our research group demonstrated for the first time the human therapeutic applications of hepatocyte-targeting GalNAc (a carbohydrate) -conjugated oligonucleotides, a platform that has revolutionized the nucleic acid-based therapeutics field with several compounds including GIVLAARI® (givosiran), which was approved for treating Acute Hepatic Porphyria in 2019. Several current examples will also be presented to illustrate the life-saving potential of RNAi (e.g., lumasiran for PH1, inclisiran for hypercholesterolemia, HBV and COVID-19).
Dan Peer, Ph. D.
Professor and Director of the Laboratory of Precision NanoMedicine, Tel Aviv University, Israel
Dan Peer is a Professor and the Director of the Laboratory of Precision NanoMedicine at Tel Aviv University (TAU). He is also the Vice President for Research and Development at Tel Aviv University, the biggest research university in Israel. From 2016 – 2020, he was the Chair of Tel Aviv University Cancer Biology Research Center that includes 17 affiliated hospitals and from 2017 – Present, he is the Founding and Managing Director of the SPARK program of Translational Medicine at TAU.
Prof. Peer’s work was among the first to demonstrate systemic delivery of RNA molecules using targeted nanocarriers to the immune system and he pioneered the use of RNA interference (RNAi) in immune cells. In addition, his lab was the first to show systemic, cell specific delivery of modified mRNA to cells to induce therapeutic gene expression of desired proteins within the immune system that has enormous implications in cancer, inflammation and infection diseases (e.g. COVID 19 mRNA vaccines). In addition, his lab was the first to show high efficiency, cell specific therapeutic genome editing in cancer. Prof. Peer has more than 130 pending and granted patents. Some of them have been licensed to several pharmaceutical companies and one is currently under registration (as a new biological drug in Inflammatory Bowel Disease). In addition, based on his work, five spin-off companies were generated aiming to bring innovative personalized medicine into clinical practice.
Prof. Peer received more than 30 awards and honors and he serves on the scientific advisory board of more than 15 companies, and on the editorial board of more than 20 journals. He is also an Associate Editor of the Journal of Controlled Release. Prof. Peer is a past President of the Israeli Chapter of the Controlled Release Society, and a Past Member of the Board of the Israel Young Academy.
RNA Therapeutics Using Targeted Lipid Nanoparticles: From Gene Silencing to Gene Editing
Accumulating work points out relevant genes and signaling pathways hampered in human disorders as potential candidates for therapeutics. Developing nucleic acid-based tools to manipulate gene expression, such as siRNAs, mRNA and genome editing strategies, open up opportunities for personalized medicine. Yet, although major progress was achieved in developing RNA targeted delivery carriers, mainly by utilizing monoclonal antibodies (mAbs) for targeting, their clinical translation has not occurred. In part because of massive development and production requirements and high batch-to-batch variability of current technologies, which relies on chemical conjugation. Here we present a self-assembled modular platform that enables to construct theoretically unlimited repertoire of RNA targeted carriers. The platform self-assembly is based on a membrane-anchored lipoprotein, incorporated into RNA-loaded lipid nanoparticles that interact with the antibody Fc domain. We show that a simple switch of 8 different mAbs, redirects specific uptake of siRNAs by diverse leukocyte subsets in vivo. The platform therapeutic potential is demonstrated in an inflammatory bowel disease model, by targeting colon macrophages to reduce inflammatory symptoms, and in Mantle Cell Lymphoma xenograft model, by targeting cancer cells to induce cell death and improve survival. In addition, I will discuss novel approach for delivering modified mRNA to specific cell types in vivo utilizing this platform. Finally, I will share new data showing very high efficiency genome editing approaches in glioma and metastatic ovarian cancer. This modular delivery platform can serve as a milestone in turning precision medicine feasible.
Wensheng Wei, Ph. D.
Professor, School of Life Sciences, BIOPIC, ICG and CLS, Peking University
Director, Peking University Genome Editing Research Center
Wensheng Wei received his bachelor degree in Biochemistry from Peking University, Ph.D. in Genetics from Michigan State University. After postdoctoral training and working as a research associate at Stanford University School of Medicine, Dr. Wei became a principle investigator in the School of Life Sciences at Peking University from 2007. He is now a professor of Biomedical Pioneering Innovation Center (BIOPIC), Beijing Advanced Innovation Center for Genomics (ICG), Peking-Tsinghua Center for Life Sciences (CLS), State Key Laboratory of Protein and Plant Gene Research, and School of Life Sciences at Peking University. The research of Wei group is mainly focused on the development of eukaryotic gene editing tools, with the emphasis on the high-throughput functional genomics and gene therapy. The combination of forward and reverse genetic means are employed, often in a high-throughput fashion, for the understanding of the molecular mechanisms underlying human diseases, including cancer and infection.
Gene Editing and High-throughput Functional Genomics
We have previously developed a series of high-throughput screening (HTS) methods based on CRISPR/Cas9 system for the functional identification of protein-coding genes and long non-coding RNAs. We have also re-designed sgRNA scaffold that greatly boosts the efficiency and data quality for HTS. Our recent efforts include the identification of functional 3D-hubs that were essential for cell viability, the development of a new approach for mapping functional sites of protein of interest at single amino acid resolution, and a series of novel high-throughput strategies derived from base editors. Besides these high-throughput strategies to facilitate the accurate and rapid identification of functional genomic elements in various settings, we have recently developed a novel programmable RNA editing strategy called LEAPER. Unlike conventional nucleic acid editing technology that requires simultaneous delivery of editing enzymes (such as Cas protein) and guide RNAs into cells, LEAPER enables precise and efficient RNA editing by recruiting endogenous cellular deaminase using engineered RNAs.
Patrick Yang Lu, Ph. D.
Founder, President and CEO of Sirnaomics, Inc., Chairman of Suzhou Sirnaomics and Guangzhou Nanotides.
Dr. Lu started his biopharmaceutical industry career in 1993 as a lab head in Novartis and was the co-founder and Executive VP of Intradigm Corporation (2001-2006). Patrick has authored more than 50 scientific papers, review articles and book chapters, and is an inventor for more than 50 issued and pending patents. He has been an invited speaker in many international conferences throughout the world and received a number of Government grants. Under his leadership, Sirnaomics has raised more than US$170 million dollars and has developed a series of “first-in-class” siRNA therapeutic candidates at different phases of clinical studies, for treatment of cancer and fibrosis diseases, in both USA and China.
Novel siRNA Therapeutics for Treatment of Cancer with Enhanced Antitumor Activity of Immune Checkpoint Inhibitor
Using a proprietary and optimized polypeptide nanoparticle (PNP) -based delivery technology, we have developed the novel anti-fibrosis and anti-cancer therapeutics with siRNAs targeting both TGFβ1 and Cox-2 simultaneously (STP705), resulting in human fibroblasts apoptosis. STP705 was initially used for local treatments for skin hypertrophic scar and non-melanoma skin cancer. An open labeled Phase IIa study using intratumoral administration results in a significant anti-cancer efficacy with completed histological clearance of tumor cells at the treatment site. While observing target knockdown in the patient biopsy samples, we also find the massive infiltration of CD8+ and CD4+ T cells into the tumor site accompany with Ki-67, LC3B and NF-κB down regulation. The histological analyses of the tissue samples revealed potential antitumor activity STP707 (a systemic formulation of STP705) was further advanced for treatment of liver fibrosis and cholangiocarcinoma, both of these indications have received Orphan drug designations by US FDA. Using a mouse syngeneic model of hepatocellular carcinoma, we tested a therapeutic potential of antitumor activity with a combination of STP707 and PD-L1 mAb. After multiple IV administrations twice a week, both single agent of STP707 and the combination treatments resulted in strong antitumor activity, more potent than those treated with Sorafenib and PD-L1 alone. Those antitumor activity were further supported by significant increase of CD8+ and CD4+ T cell infiltrations into the tumor tissue. I will discuss the unique advantage using our PNP technology platform for safe and efficient siRNA delivery, and our strategy for advancing multiple clinical studies ongoing in both USA and China.
Luciano Marraffini, Ph. D.
Professor, Rockefeller University, Investigator, HHMI, USA
Dr. Marraffini received his undergraduate degree from the University of Rosario in Argentina in 1998 and his Ph.D. from the University of Chicago in 2007, studying bacterial pathogenesis in the laboratory of Dr. Olaf Schneewind. He was a postdoc at Northwestern University from 2008 to 2010 with Dr. Erik Sontheimer, where he pioneered studies on CRISPR-Cas immunity. Dr. Marraffini determined that that CRISPR-Cas systems target DNA molecules in a sequence-specific manner, a study that was key to understand the mechanisms of CRISPR immunity at the molecular level. This finding also predicted the existence of RNA-programmable Cas nucleases and their applications. In 2010 he joined the faculty of Rockefeller University. He received the 2015 Earl and Thressa Stadtman Scholar Award from the American Society for Biochemistry and Molecular Biology, the 2015 Hans Sigrist Prize from the University of Bern, a 2017 NIH Pioneer Award and the 2017 Albany Medical Center Prize in Medicine. He became an Investigator of the Howard Hughes Medical Institute in 2018 and was elected to the National Academy of Sciences in 2019.
CRISPR-Cas13 immunity: sacrificing the host for the population
CRISPR-Cas13 protects bacterial populations from viral infections by indiscriminately destroying the RNA of the cell and its invader, simultaneously arresting the growth of infected hosts and the spread of the virus. This response is mediated by the Cas13 nuclease, which unleashes massive RNA degradation after recognition of viral transcripts that are complementary to its guide RNA. I will describe the discovery of AcrVIA1, a viral-encoded inhibitor that binds to Cas13 to occlude the RNA guide and prevent the activation of the nuclease. As opposed to inhibitors of DNA-cleaving CRISPR-Cas systems, which require multiple infections to neutralize all the Cas nucleases of the host, production of AcrVIA1 by a single virus is sufficient to overcome the CRISPR-Cas13 response.
Bing Wan, Ph. D.
Professor and Scientific Board Member, Fudan University Basic Medical College
Co-Founder of Advaccine (Suzhou) Biopharmaceutics, Co LTD.
Dr. Bin Wang is a distinguished professor at Department of Medical Microbiology and Parasitology, Fudan University School of Basic Medical Sciences. He is also a co-founder of Advaccine Biotech in China. His research area is to focus on the development of DNA vaccines against various diseases, including the SARS-CoV2, therapeutics and novel vaccine adjuvants. Those developments are achieved into several ongoing clinical trials, including a COVID 19 vaccine, an RSV vaccine, and an HBV therapeutic vaccine.
He received his B.A. in biology from Shandong University in 1982 and his Ph.D. from the Cincinnati Children Hospital at University of Cincinnati School of Medicine in 1990. He completed his postdoc training in virology and immunology at the Wistar Institute 1992. He became an instructor and then assistant professor at University of Pennsylvania Medical School in the period of 1993 to 1998. He was a professor and served as the Chairman at Department of Microbiology and Immunology for 6 years at College of Biological Sciences, China Agricultural University before he joined to Fudan University. He was one of very early DNA vaccine technology inventors in 90’s and performed the first-in human DNA vaccine trials in 1994-1996. He has published over 150 peer-review articles and awarded 35 US and 22 Chinese patents. He serves as editorial board members for several international journals and executive members in number of scientific societies.
Rapid development of a DNA vaccine against COVID-19
SARS-CoV-2, belongs to beta-coronavirus family, causing severe pneumonia and death in human namely COVID-19 has rapidly emerged as a global public health crisis. Stop the pandemic, the need to develop a safe and effective COVID-19 vaccine must be quick and easy to be manufacturing. DNA vaccine is the technology suitable for such purpose. Aiming to this goad, a task force team between China and USA was formed in January 2020, and rapid development of a DNA-based vaccine targeting the full-length of Spike protein of SARS-CoV-2 was produced. The engineered DNA vaccine induces robust expression of the Spike protein in vitro. Following immunization of mice and guinea pigs with the DNA vaccine, animals were induced antigen-specific T cell responses, functional antibodies which block and neutralize the SARS-CoV-2 infections. These vaccinated animals were well protected after SARS-CoV-2 challenges. These preclinical studies on both sides had led to Phase I and II clinical trials in both US and China. Currently, volunteers received the DNA vaccine were well tolerance and safe. This DNA vaccine is likely to be as a potential COVID-19 vaccine candidate to encounter the COVID-19 outbreak.
Zicai Liang, Ph. D.
Chairman and CEO, Suzhou Ribo Life Science Co. Ltd.
Dr. Zicai Liang is currently the Chairman and CEO of Suzhou Ribo Life Science Co. Ltd. He received his doctoral degree from Uppsala University, Sweden and postdoctoral training at Yale University, USA. He has taken faculty positions from assistant Professor to tenured Professor at Karolinska Institutet or Peking University on the subject of biotechnology with a research focus on siRNA, ncRNA and antisense ASO. He founded Ribo Life Science in 2007. Ribo is the leading RNA therapeutics company in China, with its head quarter located in the suburban of Shanghai and a research center located in Beijing. The company has established a vertically-integrated siRNA/ASO technology platform and an extensive pipeline of RNA targeting drugs. Ribo nurtured the first cross-continental collaborations between Chinese and US companies in the siRNA/ASO sub-sector, and has filed the first siRNA and first ASO clinical trials in China.
Pushing the RNA-targeting therapeutics towards bed-side in China
Although development of RNA targeting drugs in China dates back to the end of last century, all current RNA therapeutics companies were established around 2007 by returnees from US and Europe. It takes them 7 more years to witness the first-ever filing of clinical trial and two additional years to receive the first approval of the trial. Over the last five years the pace of sector towards bed-side seemed accelerated in China with eight siRNA or antisense compounds moved into various stages of clinical trials. With three siRNA or antisense trials approved for or on behalf of Ribo, and more on or approaching the filing line, Ribo Life Science has been the major driving force in the RNA targeting technology and drug development aspect in China and a main hub for international collaboration. The talk will provide an outline of the sector in China as well as Ribo’s hand-on experience in driving the technology and drug development forward in a less-optimized environment.
Adrian R. Krainer, Ph. D.
Professor at Cold Spring Harbor Laboratory and Deputy Director of Research at the CSHL
Cancer Center & Co-founder, Director, and Chair of the SAB of Stoke Therapeutics
Dr. Adrian R. Krainer is the St. Giles Foundation Professor at Cold Spring Harbor Laboratory and Deputy Director of Research at the CSHL Cancer Center. He received a Ph.D. in Biochemistry from Harvard University in 1986, working with Prof. Tom Maniatis on pre-mRNA splicing mechanisms. He continued his research on splicing as a Cold Spring Harbor Fellow, mentored by Dr. Richard J. Roberts, and joined the faculty at Cold Spring Harbor in 1989. In addition to studying splicing regulation, his laboratory is engaged in the development of mechanism-based targeted therapies to correct or modulate alternative splicing in genetic diseases and cancer. This work has resulted to date in 218 publications and seven issued patents. In collaboration with Ionis Pharmaceuticals and Biogen, Dr. Krainer’s laboratory developed nusinersen (Spinraza), which corrects the splicing defect in the SMN2 gene and became the first approved therapy for spinal muscular atrophy. Dr. Krainer is a co-founder, Director, and Chair of the SAB of Stoke Therapeutics. He was elected to the National Academy of Sciences, the National Academy of Medicine, the National Academy of Inventors, and the American Academy of Arts & Sciences. Recent awards include the 2019 Life Sciences Breakthrough Prize, the 2019 Lifetime Achievement Award of the RNA Society, the 2019 International Prize for Translational Neuroscience, the 2019 Speiser Award in Pharmaceutical Sciences, the 2020 Ross Prize in Molecular Medicine, and the 2020 Takeda & NYAS Innovators in Science Senior Scientist Award in Rare Diseases.
From Base Pairs to Bedside: Antisense Modulation of RNA Splicing
We are developing mechanism-based therapeutics, combining knowledge about RNA-splicing regulation and antisense technology. We previously developed nusinersen (Spinraza), an antisense oligonucleotide (ASO) that modulates alternative splicing of SMN2 exon 7, restoring normal levels of functional SMN protein in the context of spinal muscular atrophy (SMA). Nusinersen was approved in 2016 as the first drug for SMA; it modifies the disease course and prevents its onset if treatment is initiated pre-symptomatically. In collaboration with the Kornblihtt lab (University of Buenos Aires), we recently found that a nusinersen-like ASO promotes repressive histone marks, resulting in a more compact chromatin at the SMN2 locus; this in turn reduces the transcription-elongation rate, which promotes exon 7 skipping, opposing the ASO’s effect at the RNA level. Histone deacetylase (HDAC) inhibitors result in removal of the repressive marks and a more open chromatin, neutralizing the ASO’s inhibitory effect. Thus, HDAC inhibitors potentiate the ASO’s therapeutic effect on SMN2 splicing.
We are also developing splice-switching ASOs for cancer therapy. Pyruvate kinase M2 (PKM2) is upregulated in cancer and drives the Warburg effect. PKM2 is an alternative-splice isoform of PKM, and a potential therapeutic target. ASOs that switch PKM splicing from PKM2 to the more active PKM1isoform alter glucose metabolism and inhibit the growth of human hepatocellular carcinoma (HCC) cells. Furthermore, our lead ASO and a surrogate mouse-specific ASO inhibit tumorigenesis in orthotopic-xenograft and genetically-engineered HCC mouse models, respectively. This preclinical study establishes the potential of ASO-based PKM splice-switching as a therapy for liver cancer.
Laura Sepp-Lorenzino, Ph.D.
Executive Vice President, Chief Scientific Officer
Intellia Therapeutics, USA
Laura Sepp-Lorenzino oversees all drug research across in vivo and ex vivo (engineered cell therapy) areas as Intellia’s Chief Scientific Officer. Prior to Intellia, she was vice president, Head of Nucleic Acid Therapies, Research, and member of the External Innovation team at Vertex Pharmaceuticals, Inc. Laura previously was vice president, entrepreneur-in-residence at Alnylam Pharmaceuticals, Inc., a leader in the development of RNAi Therapeutics. At Alnylam, she was responsible for the Hepatic Infectious Disease Strategic Therapeutic Area, championed extra hepatic siRNA delivery, and was active in licensing and partnering.
Before joining Alnylam, Laura spent 14 years at Merck & Co., most recently having served as executive director and department head, RNA Therapeutics Discovery Biology. In this role, she was responsible for identification and optimization of siRNAs and delivery vehicles, advancement of preclinical candidates, and development of an siRNA-conjugate platform to expand the repertoire of tissues accessible to in vivo siRNA delivery. Laura also has expertise in oncology drug discovery and development acquired earlier in her career by leading the Cancer Research Department at Merck West Point and working as an assistant lab member and assistant attending molecular biologist at Memorial Sloan-Kettering Cancer Center.
She received her professional degree in biochemistry from the University of Buenos Aires, Argentina and both her master’s degree and doctorate in biochemistry from New York University. Laura holds professional affiliations with key scientific organizations, including the Oligonucleotide Therapeutics Society, the American Society for Gene and Cell Therapy, the European Society of Gene and Cell Therapy, and the New York Academy of Sciences, as well as a number of oncology societies.
Transforming Medicine: The Power and Promise of Genome Editing for Rare and Genetic Diseases
At Intellia, we are building a full-spectrum, product-driven biotechnology company focused on our mission of developing and commercializing potentially curative genome editing treatments that can positively transform the lives of people living with severe and life-threatening diseases. On the in vivo side, our systemic lipid nanoparticle or LNP-based delivery system has the potential to unlock treatment of genetic diseases by selectively knocking out disease-causing genes, introducing targeted insertion of a functional gene or both. We are also focused on engineering T cell therapies to provide them with particular enhanced attributes that may enable them to more effectively treat oncological and immunological diseases. Our approach is designed to improve safety and efficacy by engineering cell therapies that are more precise, potent and persistent. The CNAF presentation will focus on Intellia’s in vivo platform and pipeline, highlighting the paths to gRNA selection, preclinical pharmacology and the clinic.
Roy Parker, Ph.D.
Investigator, Howard Hughes Medical Institute
Distinguished Professor, Department of Biochemistry, University of
Colorado Boulder, USA
Roy Parker is an Investigator with the Howard Hughes Medical Institute; Executive Director, BioFrontiers Institute; Cech-Leinwand Endowed Chair of Biochemistry and Distinguished Professor at the University of Colorado Boulder. He has a joint appointment with the Department of Molecular, Cellular and Developmental Biology. He received his Ph.D. from the University of California, San Francisco and completed his Postdoctoral work at the University of Massachusetts, Worcester. His research focuses on the biogenesis, translation, and degradation of eukaryotic mRNA and how cells regulate different steps in this process to modulate gene expression. He has served on, and chaired, the NIH CDF-1 study section, and co-organized the Nucleic Acids Gordon Conference (1997), the RNA Processing Meeting at CSHL (2001), and the 2004 FASEB Conference on Post-Transcriptional Control (2004). He is, or has been, on the editorial boards of MCB, Science, Cell, RNA, Nucleic Acids Research, and is an editor of the Journal of Cell Biology and eLife. He was the President of the RNA Society (2010). He is an elected Fellow of the American Academy of Arts & Sciences (2010) and Member of the National Academy of Sciences (2012).
RNP GRANULES IN HEALTH AND DISEASE
Eukaryotic cells contain multiple assemblies of RNA and protein referred to as RNP granules, or RNP condensates. In the cytosol, ubiquitous RNP granules include stress granules, which form when translation initation is limited, and P-bodies, which are constitutive RNP granules containing mRNAs and the RNA decay machinery. Both stress granules and P-bodies contain complex proteomes and transcriptomes and their assembly/disassembly are regulated by diverse RNP remodeling complexes.
Focusing on stress granules, we have provided evidence that stress granule, and presumably other RNP condensate, assembly occurs in part through intermolecular RNA-RNA interactions. However, based on in vitro studies, we demonstrate that RNA condensation should be expected to be a thermodynamically favored process in cells. This argues cells must contain mechanisms to limit RNA driven condensation. We have demonstrated that abundant RNA helicase reduces RNA recruitment to RNA condensates in vitro and in cells, as well as limiting stress granule formation. This defines a new function for abundant RNA helicases to limit thermodynamically favored intermolecular RNA-RNA interactions in cells as “RNA decondenases”, thereby allowing proper RNP function.
Anna Collen, Ph.D.
Senior Project Leader, Projects, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
Anna holds a PhD in Biochemistry at Lund University and joined AstraZeneca in 2001. Before joining AZ Anna spent time at a small biotech in Copenhagen, ALK with antigen production for immunization of humans and one of the world leading technology institutes, VTT in Helsinki, Finland with large scale protein production in collaboration with Genencore, US. Anna has held a number of increasingly senior positions at AstraZeneca within Therapy Areas early science units, spanning from early discovery to late development and life cycle management. Anna is in the last 5 years involved in the mRNA project in collaboration with Moderna where she currently is the project lead for the novel project utilizing mRNA encoding for VEGF for cardiac regeneration.
VEGF-A modified mRNA in Cardiovascular Disease
AstraZeneca has over the last years developed a therapeutic drug of Vascular Endothelial Growth Factor (VEGF-A) mRNA, known as AZD8601. This has been performed in partnership with Moderna Therapeutics, Inc. VEGF-A is a well-studied protein known to stimulate angiogenesis. Intracardiac delivery of modified mRNA encoding for VEGF-A achieve a local transient expression of VEGF-A, and this is thought to improve ventricular function in patients following a myocardial infarction. The final aim is to regenerate damaged heart tissue and treat patients. Pre-clinical and clinical data from the Ph1study will be presented. The EPICCURE Ph2a study in CABG patients is on-going and the future plans for the mRNA VEGF-A project is to be discussed.
Zhenjun Yang, Ph.D.
Professor, State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China.
Prof. Zhenjun Yang (PhD) was born and raised in Jilin province, China. He received his B.S. degree and Ph.D. degree in pharmaceutical chemistry from Beijing Medical University in 1987 and 1998. He worked as a postdoctoral research fellow at college of pharmacy in University of Georgia in 2000-2002. From 2002, he is working as an associate professor and a professor (2008), Director of Nucleic Acid Research Group, in State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University. His principal research directions include: 1. Encapsulation and modification of antisense oligonucleotides, aptamers and siRNAs; 2. Techniques based on aptamers for disease detection; 3. Chemical biology research of cyclic dinucleotides; 4. Nucleoside antiviral drugs. He is the committee member of Chemical Biology Division, also Chemical Education Division, in Chinese Chemical Society.
Chemical Biology of Functional Oligonucleotides Encapsulated by Neutral Cytidinyl Lipid
A neutral cytidinyl lipid DNCA was used to encapsulate the nucleolin aptamer AS1411 and the thrombin aptamer TBA, via H-bonding or π-π interaction, showed selective antitumor activity against drug resistant cell line at concentration of 100 nM. By iTRAQ-based quantitative proteomics analysis and Bio-Layer Interferometry (BLI) etc., it has been identified that they target to hnRNP A1, which is over expressed in nucleus of drug resistant tumor cells, indirectly influence G-4 unfolding of Kras promptor, leading to KRAS pathway and tumor growth inhibition. Antisense oligonucleotides (ASOs) usually contain a fully phosphorothioate (PS) backbone, such as G3139, an ASO targets Bcl-2, encapsulated by DNCA and a cationic lipid CLD (mix) showed IC50 0.158 μM against MCF-7/ADR. Also, LNA modified G3139 (LNA-G3139) showed superior antiproliferation (78.5%) and Bcl-2 mRNA suppression (85.5%) at 200 nM. More apoptosis associated mRNA targets have been also identiﬁed in MCF-7/ADR. The strategy has been also applied to the encapsulation of siRNA, which have results excellent data. Based on thus results, modified AS1411, TBA and LNA-G3139 etc. could further be clinically applied in the future.
Biliang Zhang, Ph.D.
President, Guangzhou RiboBio Co., Ltd.
Biliang Zhang received his M.S. in Organic Chemistry from Fordham University in 1990, Ph.D. in Organic Chemistry with Prof. Ronald Breslow at Columbia University in 1995, and conducted his post-doctoral training with Prof. Thomas Cech at University of Colorado Boulder. In 1998 Dr. Zhang became an Assistant Professor of the Program in Molecular Medicine at University of Massachusetts Medical School. In 2004 he accepted a Principal Investigator role at the Guangzhou Institute of Biomedicine and Health of Chinese Academy of Sciences, where he currently holds a Professor position. Using diverse biological and chemical methodologies, Dr. Zhang’ s lab studies the roles of RNA molecules in living cells. His particular interests are in the fields of non-coding RNAs, nucleic acid syn thetic biology and therapeutics. In 2004, Dr. Zhang established Guangzhou RiboBio Co., Ltd.
mRNA Vaccine and Manufacturing
In Vitro Transcribed (IVT) mRNA has recently come into focus as a potential new drug class. Therapeutic use of mRNA is promising for cancer immunotherapy, vaccination against infectious diseases, and replacement therapy as well as regenerative medicine. The mRNA vaccine field is developing extremely rapidly, a large body of preclinical data has accumulated over the past several years, and multiple human clinical trials have been initiated. However, the scalable manufacturing of mRNA is a challenge for the commercialization of mRNA drugs and vaccines.
RiboBio’s extensive experience, professional knowledge, and reliable quality are highly recognized by customers in the oligonucleotide and RNA field. RiboBio is committed to providing customers with RNA drug process, analysis, CMC, API, and commercial manufacturing services. Through collaboration with global pharmaceutical companies, RiboBio enables more and more innovative RNA drugs to enter clinical phases and then to the markets that will ultimately benefit the world.