
MicroRNAs: A Gene Silencing Mechanism with Therapeutic Implications
Wednesday, July 13, 2016
The New York Academy of Sciences
MicroRNAs (miRNAs) are single-stranded RNAs about 22 nucleotides in length that repress the expression of specific proteins by annealing to complementary sequences in the 3′ untranslated regions (UTRs) of target mRNAs. Apart from their posttranscriptional expression, or silencing, miRNAs may also direct mRNA destabilization and cleavage. Moreover, rather than targeting a single disease-associated protein target as many small molecule drugs and antibodies do, each miRNA may serve to repress the expression of numerous proteins involved in the pathogenesis and progression of various diseases and could therefore potentially interfere with multiple disease-promoting signal transduction pathways. Because aberrant expression of miRNAs has been implicated in numerous disease states, miRNA-based therapies have sparked much interest for the treatment of a variety of diseases. The objective of this symposium is to bring together investigators who have led the field in describing what miRNAs do and their potential in treating diseases, as well as those who are translating these findings into promising drug candidates, some of which have already advanced into early stage clinical trials.
* Reception to follow.
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Nonmember (Academia) | $105 |
Nonmember (Corporate) | $160 |
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Nonmember (Student / Postdoc / Resident / Fellow) | $70 |
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This event will also be broadcast as a webinar; registration is required.
Please note: Transmission of presentations via the webinar is subject to individual consent by the speakers. Therefore, we cannot guarantee that every speaker's presentation will be broadcast in full via the webinar. To access all speakers' presentations in full, we invite you to attend the live event in New York City where possible.
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Member (Student / Postdoc / Resident / Fellow) | $0 |
Nonmember (Academia) | $20 |
Nonmember (Corporate) | $35 |
Nonmember (Non-profit) | $20 |
Nonmember (Student / Postdoc / Resident / Fellow) | $10 |
Agenda
* Presentation times are subject to change.
Wednesday, July 13, 2016 | |
8:30 AM | Registration and Continental Breakfast |
9:00 AM | Welcome and Opening Remarks |
9:10 AM | Keynote Presentation: MicroRNAs |
Plenary Session I: MicroRNAs in Cancer | |
9:55 AM | MicroRNA-based Therapeutics in Cancer |
10:30 AM | Inhibition of MicroRNAs by Anti-miRs to Treat Human Disease |
11:05 AM | Networking Coffee Break |
11:35 AM | Using Mouse Models to Functionally Dissect an Oncogenic MiRNA Cluster |
12:10 PM | Structural Effects of SNPs in Human MiRNA Targets |
12:25 PM | MicroRNA-30c Mimic Mitigates Hypercholesterolemia and Atherosclerosis in Mice |
12:40 PM | Networking Lunch and Poster Session |
Plenary Session II: Therapeutic Applications of MicroRNA Technologies | |
2:15 PM | Targeting the Immune Microenviroment with RNA Therapeutics |
2:50 PM | Modular Degradable Dendrimers Enable Therapeutic MiRNAs to Extend Survival in an Aggressive Liver Cancer Model |
3:25 PM | Networking Coffee Break |
3:55 PM | Combining Radiation Therapy and MicroRNA Therapeutics: Preclinical Assessment and Translational Approaches |
4:30 PM | Poster Prize Presentation and Closing Remarks |
4:40 PM | Networking Reception |
5:40 PM | Adjourn |
Organizers
Lynn M. Abell, PhD
Bristol-Myers Squibb
Andreas G. Bader, PhD, MSc
Mirna Therapeutics, Inc.
David Brown, PhD
Mirna Therapeutics, Inc.
David Brown serves as VP of Preclinical Pharmacology at Mirna Therapeutics and has worked with the company since its inception in 2008. Previously, Dr. Brown was the Director of Discovery at Asuragen, Inc., where he oversaw efforts to identify diagnostic and therapeutic applications for microRNAs. Prior to joining Asuragen, Dr. Brown worked for ten years as a senior scientist and Director of R&D at Ambion, Inc. Dr. Brown received his PhD in molecular biology from the University of Colorado.
Sonya Dougal, PhD
The New York Academy of Sciences
Paul Lammers, MD MSc
Mirna Therapeutics, Inc.
Paul Lammers, MD, MSc, joined Mirna Therapeutics in November 2009 as its President, CEO, and Director of the Board. Since joining the company, Paul has led the team in successfully raising more than 150 million dollars for the company, both from leading traditional and corporate venture firms, Federal and State grant programs, including the Texas Emerging Technology Fund (ETF) and the Cancer Prevention and Research Institute of Texas (CPRIT), and by recently bringing the company public (NASDAQ: MIRN). Prior to joining Mirna Therapeutics, Dr. Lammers served as President of Repros Therapeutics in The Woodlands, Texas, after having served for 6 years as the Chief Medical Officer for EMD Serono Inc., a Division of German pharmaceutical company, Merck KgA. He began his career with Dutch pharmaceutical company, Organon, spending 8 years in the commercial and clinical operations in Europe and the US. He also served 4 years as Senior Vice President of clinical and regulatory affairs at Zonagen in The Woodlands, TX. Dr. Lammers obtained his Medical and Masters of Science degrees from Radboud University in Nijmegen, The Netherlands, and moved with his family to the US in 1992.
Caitlin McOmish, PhD
The New York Academy of Sciences
George Zavoico, PhD
JonesTrading Institutional Services
George B. Zavoico, PhD, is a Senior Equity Analyst, Healthcare, at JonesTrading Institutional Services, a leading equity trading firm with a focus on block trading and a growing capital markets business. He has over 11 years of experience as a life sciences analyst writing research on publicly traded equities. His principal focus is on biotechnology, biopharmaceutical, specialty pharmaceutical, and molecular diagnostics companies. He received The Financial Times/Starmine Award two years in a row for being among the top-ranked earnings estimators in the biotechnology sector. In 2009, Zavoico was hired as the first equity analyst at MLV & Co., a New York-based boutique investment bank and institutional broker-dealer at the time, where he helped establish its Healthcare research team. He returned to MLV in mid-2014 after serving for a brief period as a Senior Equity Analyst at H.C. Wainwright & Co. in early 2014, and then joined JonesTrading in early 2015. Previously, Zavoico was an equity research analyst in the healthcare sector at Westport Capital Markets and Cantor Fitzgerald. Prior to working as an analyst, Zavoico established his own consulting company serving the biotech and pharmaceutical industries, providing competitive intelligence and marketing research, due diligence services and guidance in regulatory affairs. Zavoico began his career as a senior research scientist at Bristol-Myers Squibb Co., moving on to management positions at Alexion Pharmaceuticals Inc. and T Cell Sciences Inc. (now Celldex Therapeutics Inc.). Zavoico has a bachelor's degree in biology from St. Lawrence University and a Ph.D. in physiology from the University of Virginia. He held post-doctoral fellowships at the University of Connecticut School of Medicine and Harvard Medical School/Brigham & Women's Hospital. He has published more than 30 papers in peer-reviewed journals and has coauthored four book chapters.
Keynote Speaker
David Bartel, PhD
Whitehead/MIT/HHMI
David Bartel received his PhD from Harvard in 1993 and has since headed a lab at the Whitehead Institute for Biomedical Research, where he is also an Investigator of the Howard Hughes Medical Institute and a Professor of Biology at MIT. His lab initially studied the ability of RNA to catalyze reactions and more recently has focused on RNAs that regulate gene expression. Over the past 16 years his lab has helped define microRNAs and other types of small regulatory RNAs and has contributed to the understanding of their genomics, biogenesis and regulatory targets, as well as the molecular and biological consequences of their actions in animals, plants and fungi.
Speakers
Maria Angelica Cortez, PhD
The University of Texas MD Anderson Cancer Center
Maria Angelica received her master's and Ph.D degree from University of Sao Paulo, Brazil, in 2009. She completed part of her thesis at Dr. George Calin laboratory at MD Anderson, where she devoted her thesis to understanding the roles of noncoding RNAs, including microRNAs, in the molecular mechanisms underlying tumor progression. She joined Dr. Welsh's lab as a postdoctoral fellow in 2011 and was appointed Instructor at the Department of Radiation Oncology in 2015. Dr. Cortez's long-term career goal is to discover novel therapeutic strategies involving microRNAs to target immunotherapy resistant lung and breast cancer cells. Her current projects include: 1) understanding the mechanisms by which tumors evade the immune system, and 2) exploring the interaction between radiation and microRNA therapeutics for the treatment of lung cancer.
Paul Grint, MD
Regulus Therapeutics
Dr. Grint joined Regulus in June 2014 as Chief Medical Officer and was appointed President and Chief Executive Officer in June 2015. Dr. Grint has over two decades of experience in biologics and small molecule development, including the successful commercialization of numerous commercial products in oncology, anti-infectives and immunology in both domestic and international markets. Prior to joining Regulus, Dr. Grint was President of Cerexa, Inc., a wholly-owned subsidiary of Forest Laboratories, Inc., where he was responsible for the oversight of anti-infective product development. Prior to that, Dr. Grint served as Senior Vice President of Research at Forest Research Institute, Inc., Chief Medical Officer at Kalypsys, Inc., and Senior Vice President and Chief Medical Officer at Zephyr Sciences, Inc., and he also served in similar executive level positions at Pfizer Inc., IDEC Pharmaceuticals Corporation, and Schering-Plough Corporation. Dr. Grint received his bachelor's degree from St. Mary's Hospital in London and his medical degree from St. Bartholomew's Hospital Medical College at the University of London. Dr. Grint is a Fellow of the Royal College of Pathologists, a member of numerous professional and medical societies, and the author or co-author of over fifty scientific publications.
David S. Hong, MD
The University of Texas MD Anderson Cancer Center
Daniel J. Siegwart, PhD
University of Texas Southwestern Medical Center
Daniel J. Siegwart is an Assistant Professor in the Simmons Comprehensive Cancer Center and Department of Biochemistry at the University of Texas Southwestern Medical Center (UTSW). He received a BS in Biochemistry from Lehigh University in 2003, and a PhD in Chemistry from Carnegie Mellon University (CMU) in 2008 under the supervision of University Professor Krzysztof Matyjaszewski. During his graduate studies, he received the Joseph A. Solomon Memorial Fellowship in Chemistry at CMU and was a National Science Foundation East Asia and Pacific Summer Institutes Fellow at the University of Tokyo in 2006 with Prof. Kazunori Kataoka. Dan then completed a National Institute of Health sponsored Postdoctoral Fellowship at Massachusetts Institute of Technology with Institute Professor Robert Langer (2008–2012). Dan began his independent research career in 2012 at UTSW. The Siegwart Research Group's long-term goals are to develop new materials for therapeutic nucleic acid delivery (siRNA, miRNA, mRNA, CRISPR sgRNA), develop new polymers to deliver chemotherapeutic drugs to hypovascular tumors, develop theranostic "turn on" probes, and to globally understand how the physical and chemical properties of materials affect interactions with biological systems in vitro and in vivo in the context of improving cancer therapies. They aspire to utilize chemistry and engineering to make a beneficial impact on human health through improved cancer therapies.
Frank Slack, PhD
BIDMC Cancer Center/Harvard Medical School
Frank Slack, PhD, is Director of the Institute for RNA Medicine at Beth Israel Deaconess Medical Center (BIDMC). He is a Professor of Pathology.
Frank Slack received his BSc from the University of Cape Town in South Africa, before completing his PhD in molecular biology at Tufts University School of Medicine. He started work on microRNAs as a postdoctoral fellow in Gary Ruvkun's laboratory at Harvard Medical School, where he co-discovered the second known microRNA, let-7 and the first human microRNA. He subsequent moved to the Department of Molecular, Cellular and Developmental Biology at Yale University, where he was a program leader in the Yale Cancer Center, and the Director of the Yale Center for RNA Science and Medicine. There he discovered that microRNAs regulate key human oncogenes and have the potential to act as therapeutics. He also demonstrated the first role for a microRNA in the aging process. In 2014 he became Director of the Institute for RNA Medicine and a Professor of Pathology at BIDMC.
Dr. Slack studies the roles and uses of microRNAs and their targets in development, disease and aging. He has been at the forefront of the small RNA revolution. He was in the team that discovered the first human microRNA, let-7 and subsequently showed that it is a tumor suppressor that controls key cancer genes, such as RAS, MYC and LIN28. They are developing let-7 and a second microRNA, miR-34 as novel cancer therapeutics with miR-34 already in Phase I clinical trials. They also proved that microRNAs act as key oncogenes and developed strategies to target these oncomiRs for cancer therapy. Their research also extends to discovery of additional novel small RNAs in development, cancer, aging and diabetes as well as identifying novel SNPs in the non-coding portions of the genome with an eye to identifying the next generation of actionable targets in cancer.
Dr. Slack was an Ellison Medical Foundation Senior Scholar and received the 2014 Heath Memorial Award from MD Anderson Cancer Center.
Joana Vidigal, PhD
Memorial Sloan Kettering Cancer Center
Dr. Vidigal received her PhD from the Free University of Berlin in 2011, where she developed an inducible RNAi platform to study mouse embryogenesis. Since then, as a research fellow in the lab of Andrea Ventura at Memorial Sloan Kettering Cancer Center, she has been focused on understanding the role of noncoding elements—and in particular miRNAs—in controlling gene expression, and how their deregulation can contribute to disease. Using an allelic series of genetically engineered mouse models, Dr. Vidigal helped define the functional contributions of individual components of the oncogenic miR-17~92 cluster to the regulation of mammalian development and tumor progression. She is currently establishing CRISPR-Cas9 tools to functionally query the noncoding genome in a high-throughput manner.
Dr. Vidigal is a recipient of the 2016 Memorial Sloan Kettering Postdoctoral Research Award.
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This program is supported by an educational grant from Bristol-Myers Squibb.
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Abstracts
MicroRNAs
David Bartel, PhD, Howard Hughes Medical Institute, Whitehead Institute, and Massachusetts Institute of Technology
We study the molecular pathways that affect the stability or translation of mRNAs and thereby regulate eukaryotic gene expression. This talk will focus microRNAs (miRNAs) and two different ways that they can mediate post-transcriptional repression. When a miRNA pairs to a site with extensive complementarity, it can direct Argonaute-catalyzed slicing of the mRNA, provided that the miRNA is associated with a slicing-competent version of the Argonaute protein. We have recently found that this type of repression does not occur in many vertebrate species, which explains why gene-knockdown methods that try to exploit this activity have been ineffective in these species. The other type of repression is through a mechanism that does not involve slicing but nonetheless does reduce the mRNA level. This mechanism occurs at sites with less extensive complementarity and involves recruitment of deadenylase enzymes that shorten the poly(A) tail of the mRNA, thereby triggering de-capping and mRNA decay. In an effort to better understand this type of targeting, which dominates in humans and other bilaterian animals, we are analyzing high-throughput biochemical results that simultaneously compare the relative affinities and elemental rate constants of many thousands of pairing possibilities. The ability to simultaneously evaluate so many different miRNA-target pairing possibilities complements the biochemistry that has been done with individual sequences and is providing insights that are helping us to better predict miRNA targets.
MicroRNA-Based Therapeutics in Cancer
Frank J. Slack, PhD, Department of Pathology, BIDMC/Harvard Medical School
MicroRNAs are small non-coding RNAs that regulate gene expression to control important aspects of development and metabolism such as cell differentiation, apoptosis and lifespan. miR-21, miR-155, let-7 and miR-34 are microRNAs implicated in human cancer. Specifically, human let-7 and miR-34 are poorly expressed or deleted in lung cancer, and over-expression of let-7 or miR-34 in lung cancer cells inhibits their growth, demonstrating a role for these miRNAs as tumor suppressors in lung tissue. let-7 and miR-34 regulate the expression of important oncogenes implicated in lung cancer, suggesting a mechanism for their involvement in cancer. We are focused on the role of these genes in regulating proto-oncogene expression during development and cancer, and on using miRNAs to suppress tumorigenesis. In contrast, miR-21 and miR-155 are oncomiRs and up-regulated in many cancer types. We are also developing effective strategies to target these miRNAs as a novel anti-cancer approach. Lastly we are examining the non-coding portions of the genome for mutations and variants that are likely to impact the cancer phenotype. We have successfully resequenced the 3′UTRome and microRNAome from cancer patients with a family history of cancer.
Inhibition of MicroRNAs by Anti-miRs to Treat Human Disease
Paul Grint, MD, Regulus Therapeutics, San Diego
Anti-miRs are single-stranded synthetic oligonucleotides that sequester a target microRNA (miR) in diseased cells to form an inactive heteroduplex. RG-101 is a potent hepatocyte targeted N-acetylgalactosamine (GalNAc)-conjugated anti-miR-122 oligonucleotide that inhibits the interaction of HCV with a host factor miR. miR-122 is the most abundant miR in the liver and is required for replication by the hepatitis C virus (HCV), binding to specific regions in the 5′ untranslated region (UTR) of the viral genome. GalNAc conjugation affords preferential targeting of RG-101 to hepatocytes by high affinity binding to asialoglycoprotein receptors expressed on hepatocytes that are responsible for removal of target glycoproteins from the systemic circulation. Once taken up into hepatocytes, RG-101 is metabolized to its active unconjugated anti-miR (RG1649).
In a Phase 1 clinical trial, a single sub-cutaneous administration of RG-101 produced mean viral load reductions of 4.8 log (4 mg/kg) and 4.1 log (2 mg/kg) in patients chronically infected with either HCV genotype (GT) 1, 3, or 4 at day 29.
Current HCV standard of care treatment consists of 8–12 weeks of direct acting antiviral (DAA) oral agents. We are studying the safety and efficacy of a 4 week combination treatment regimen of RG-101 plus oral direct acting antivirals (DAAs) in HCV genotype 1 and 4 patients. Treatment naïve, non-cirrhotic patients with chronic GT1 or 4 HCV infection were enrolled. Each patient received a 2 mg/kg subcutaneous (SC) injection of RG-101 on Day 1, with 4 weeks of an oral DAA (either ledipasvir/sofosbuvir, simeprevir, or daclatasvir), followed by a second 2 mg/kg SC injection of RG-101 on Day 29. Interim analysis was performed to assess sustained virologic response at week 12 post-treatment (SVR12). Response was defined as an HCV RNA level below the lower limit of quantification (LLOQ) using the Abbott RealTime HCV Assay (LLOQ=12 IU/mL).
Seventy-nine patients were enrolled and received study therapy. Baseline disease characteristics were balanced across treatment arms. Mean age was 45.0 years, 54% were female, and mean baseline viral load was 5.805 (log10) IU/ml. 77% of patients had HCV Gt1 (20% Gt1a, 53% Gt1b) and the majority (86%) had stage 0–1 fibrosis by Fibroscan®. Combination therapy was generally well tolerated. Most adverse events (AEs) were mild or moderate in intensity and there were no discontinuations due to AEs.
SVR12 was achieved by 100% of patients (27/27) in the RG-101 + ledipasvir/sofosbuvir; 26/27 [96%] in the RG-101 + simeprevir arm; and 22/24 [92%] in the RG-101 + daclatasvir arm. Long-term safety and efficacy through Week 48 of post-treatment follow-up is ongoing.
These interim results indicate the potential for RG-101 plus DAA combination therapy to provide a curative HCV regimen with 4 weeks of treatment.
Using Mouse Models to Functionally Dissect an Oncogenic MiRNA Cluster
Joana Vidigal, PhD, Memorial Sloan Kettering Cancer Center
Polycistronic microRNA (miRNA) clusters are a common feature of vertebrate genomes, but the level of functional cooperation among their individual components remains poorly understood. In this talk I will discuss our recent efforts to address this question using an allelic series of genetically engineered mice, each harboring a selective targeted deletion of individual components of the oncogenic miR-17~92 cluster. Our results demonstrate the coexistence of functional cooperation and specialization among members of this polycistron, identify a previously undescribed function for the miR-17 seed family in controlling axial patterning in vertebrates, and show that loss of miR-19 selectively impairs Myc-driven tumorigenesis in two models of human cancer. Our work provides a genome-wide view of how the components of a polycistronic miRNA cluster affect gene expression in vivo, and offers a strong rational for the therapeutical inhibition of miR-19 in Myc-driven tumors. I will also discuss our efforts to adapt novel genome editing tools to the study of noncoding genes.
Combining Radiation Therapy and Immunomodulatory MicroRNAs: Preclinical Assessment and Translational Approaches
Maria Angelica Cortez, PhD, The University of Texas MD Anderson Cancer Center
Therapeutic resistance is the primary factor that limits the effectiveness of current therapies for solid tumors. Strategies for overcoming this resistance should readily translate into improved outcomes. This concept is particularly relevant for overcoming resistance to ionizing radiation, which is currently the only potentially curative nonsurgical approach for most solid tumors. Therapeutic delivery of synthetic microRNAs (miRNAs) that mimic endogenous tumor suppressor miRNAs has emerged as a promising approach for treating cancer. MiRNAs target multiple cellular processes and thus in theory can have broad effects beyond current approaches that are limited to targeting single aspects of a cellular pathway. The ability to inhibit oncogenic miRNAs or replace them with tumor suppressor miRNAs may complement traditional treatments such as chemotherapy and radiation. However, the role of miRNAs in mediating resistance to radiotherapy is poorly understood. Therefore, the ultimate goal is to assess the potential applicability of miRNA delivery in combination with radiation therapy. Furthermore, the immune-modulating effects of radiation therapy have recently gained considerable interest and there have been multiple reports of synergy between radiation and immunotherapy. We previously found that immunomodulatory miRNAs, such as miR-200 and miR-34a, can help to overcome resistance to radiation. We next generated a preclinical tumor model resistant to radiation and immunotherapy and identified upregulation of miRNAs as an underlying mechanism by which some tumors do not respond to immunotherapy. Our future goal is to validate these findings in our ongoing clinical studies.
Dendrimer Nanoparticle-Mediated Delivery of let-7g MiRNA Extends Survival in Mice Bearing MYC-Driven Cancer
Daniel J. Siegwart, PhD, The University of Texas Southwestern Medical Center
MicroRNA-based cancer therapies are hindered by the lack of delivery vehicles that avoid cancer-induced organ dysfunction which exacerbates carrier toxicity. We addressed this issue by developing modular degradable dendrimers that achieved the required combination of high potency to tumors and low hepatotoxicity to provide a pronounced survival benefit in an aggressive genetic cancer model. >1,500 Dendrimers were synthesized using sequential, orthogonal reactions where ester degradability was systematically integrated with chemically diversified cores, peripheries, and generations. A lead dendrimer, called 5A2-SC8, provided a broad therapeutic window. It was identified as being potent (EC50 < 0.02 mg/kg siFVII) in dose response experiments, and well tolerated in separate toxicity studies in chronically ill mice bearing MYC-driven tumors (>75 mg/kg dendrimer repeated dosing). Delivery of let-7g miRNA mimic inhibited tumor growth and dramatically extended survival. Efficacy stemmed from a combination of a small RNA with the dendrimer's own negligible toxicity, therefore illuminating an underappreciated complication in treating cancer with RNA-based drugs.
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