第四届广州核酸国际论坛

2016年11月9-10日 , 广州科学城

议题介绍

核酸科学是当前国际生物医学领域的前沿和热门研究方向,发展迅速,对推动精准医学研究和人类健康起到重要作用。为了推动国内核酸科学和产业的整体发展,推动国内与全球核酸科学研究领域的整合,我们已经成功发起举办三届广州核酸国际论坛。历届论坛演讲嘉宾均由诺贝尔奖得主领衔,汇聚全球核酸领域知名专家学者,议题涵盖医疗、科研及工业等领域的研究热点和最新进展,旨在为中外科学家提供一个高端交流平台,共同分享和探讨本领域的最新研究成果、应用前景及产业化方向。论坛的知名度和影响力得到广大参会人员的高度认可,被誉为核酸研究领域学术风向标。 2016年我们将迎来第四届广州核酸国际论坛的召开,本届论坛将邀请世界顶尖科学家及知名企业家齐聚一堂,与您分享本领域的最新成果和进展。本届论坛主题如下:

1、非编码RNA国际研究前沿

2、尖端核酸技术开发与应用

3、核酸诊断与标志物发现

4、核酸治疗与药物开发

论坛议程

Day 1 Wednesday, November 09

08:45-08:55

Opening

 Organizers

08:55-09:00

Chair

 Mikiko SIOMI, PhD

09:00-09:45

Keynote

 Ada YONATH, PhD, Professor, Weizmann Institute of Science, Israel Nobel Prize in Chemistry 2009
 Title: Combating resistance to antibacterial and anti-parasite ribosomal antibiotics?

09:45-10:15

 

 Chuan HE, PhD, Professor, University of Chicago, USA
 Title:
 New sequencing technology to map DNA epigenetic modifications

10:15-10:45

Tea Break

10:45-11:15

 

 Erik SONTHEIMER, Professor, University of Massachusetts Medical School
 Title:
 Genetic Interference and Genome Editing by Neisseria meningitidis Cas9

11:15-11:45

 

 Jin-Soo KIM, PhD, Director, Institute for Basic Science, South Korea
 Title:
 CRISPR RNA-guided Genome Editing in Human Stem Cells, Animals, and Plants

11:45-12:00

Technology

 TBD 
 Title:

12:00-13:30

Lunch

13:30-13:35

Chair

 Muthiah MANOHARAN, PhD

13:35-14:20

Keynote

 Howard CHANG, MD, PhD, Professor, Stanford University, US
 Title:
 Genome Regulation by Long Noncoding RNAs

14:20-14:50

 

 Judy LIEBERMAN, MD, PhD, Professor, Harvard Medical School, USA
 Title:
 The Silent Treatment: Targeted gene knockdown

14:50-15:20

Tea Break

15:20-15:50

 

 Troels KOCH, PhD, VP and Head of Research,Roche, Denmark / Switzerland
 Title:
 New perspectives in LNA therapeutics

15:50-16:20

 

 Jian-Sheng SUN, PhD, HDR, Professor, Muséum National d’Histoire Naturelle, France
 Title:
 Signal interfering DNA (siDNA): from an original concept to a promising a first-in-class DNA 
            repair inhibitor against advanced stage cancer in patients

16:20-16:50

 

 Mark EDBROOKE, PhD, Director, AstraZeneca, UK
 Title:
 Therapeutic nucleic acids including antisense oligonucleotides – significant progress towards a
            viable drug platform for tackling intractable targets in oncology

17:00-17:30

 After-Hours Social

Day 2 Thursday, November 10

08:55 – 09:00

Chair

 Elizabeth TRAN, PhD

09:00-09:45

Keynote

 Craig C. Mello, PhD, Professor, University of Massachusetts, 2006 Nobel Prize Winner, USA
 Title:
 RNA-guided inheritance

09:45-10:15

 

 Mikiko SIOMI, PhD, Professor, the University of Tokyo, Japan
 Title:
 PIWI-interacting RNAs in animals

10:15-10:45

Tea Break

10:45-11:15

 

 Robert HOLT, PhD, Professor, University of British Columbia, Canada
 Title:
 Towards personalized T cell receptor therapeutics: Interrogating the T cell repertoire

11:15-11:45

 

 Muthiah MANOHARAN, PhD, Senior Vice President, Alnylam Pharmaceuticals, USA
 Title:
 RNAi Therapeutics in Human Disease using GalNAc-siRNA Conjugates: How sweet it is to work
            with sugars

11:45-12:00

Technology

 TBD 
 Title:

12:00-13:30

Lunch

13:30-13:35

Chair

 Mark EDBROOKE, PhD

13:35-14:20

Keynote

 Stanley CROOKE, MD, PhD, Founder, CEO and Chairman of the Board lonis Pharmaceuticals, USA
 Title:
 Antisense Technology: Past, Present, Future

14:20-14:50

 

 Yi-Tao YU, PhD, Professor, University of Rochester, USA
 Title:
 RNA-guided RNA Modifications

14:50-15:20

Tea Break

15:20-15:50

 

 Elizabeth TRAN, PhD, Associate Professor,Purdue University, USA
 Title:
 Long Non-Coding RNAs Regulate Gene Expression Through Formation Of RNA-DNA Hybrids

15:50-16:20

 

 Jan Gorodkin, PhD, Professor,University of Copenhagen, Denmark
 Title:
 Computational analysis of RNA structure and interactions in genomic sequence

16:20-16:50

 

 Ekkehard LEBERER, PhD, Professor, Senior Director, Sanofi, Germany
 Title:
 MicroRNA therapeutics for targeting the pathways of human disease

16:50-17:00

Closing

 Craig C. Mello, PhD, Professor, University of Massachusetts, 2006 Nobel Prize Winner, USA

论坛赞助与合作媒体

金牌赞助

 

 

银牌赞助

 

 

铜牌赞助

专项赞助

 

 

 

 

合作媒体


演讲嘉宾

Howard CHANG, MD, PhD

Professor, Stanford University, USA

Howard Hughes Medical Institute

Howard Y. Chang M.D., Ph.D. is Director of the Center for Personal Dynamic Regulomes and Professor of Dermatology at Stanford University School of Medicine. Chang earned a Ph.D. in Biology from MIT, M.D. from Harvard Medical School, and completed Dermatology residency and postdoctoral training at Stanford University. His research addresses how large sets of genes are turned on or off together, which is important in normal development, cancer, and aging. Chang discovered a new class of genes, termed long noncoding RNAs, can control gene activity throughout the genome, illuminating a new layer of biological regulation. He has invented new methods for defining the shapes of RNA and DNA genome-wide. The long term goal of his research is to decipher the regulatory information in the genome to benefit human health.

Dr. Chang’s honors include the Paul Marks Prize for Cancer Research, Judson Daland Prize of the American Philosophical Society, Howard Hughes Medical Institute Early Career Scientist, the Vilcek Prize for Creative Promise, Alfred Marchionini Research Prize, American Cancer Society Research Scholar Award, Damon Runyon Scholar Award, and elected membership to the American Society for Clinical Investigation. His work was honored by the journal Cell as a Landmark paper over the last 40 years and by Science as “Insight of the decade”.

Presentation Title

Genome Regulation by Long Noncoding RNAs

Summary

The discovery of extensive transcription of long noncoding RNAs (lncRNAs) provide an important new perspective on the centrality of RNA in gene regulation. I will discuss genome-scale strategies to discover and characterize lncRNAs. An emerging theme from multiple model systems is that LncRNAs form extensive networks of ribonucleoprotein (RNP) complexes with numerous chromatin regulators, and target these enzymatic activities to appropriate locations in the genome. Consistent with this notion, long noncoding RNAs can function as modular scaffolds to specify higher order organization in RNP complexes and in chromatin states. The importance of these modes of regulation is underscored by the newly recognized roles of long RNAs in human diseases.

Stanley CROOKE, MD, PhD

Founder, CEO and Chairman of the Board

Ionis Pharmaceuticals, USA

Dr. Crooke is one of the pioneers, most experienced scientists and knowledgeable experts in the oligonucleotide therapeutics field. He established and for more than 20 years supervised drug discovery and development platform, resulting in growing number (currently nearly 30) of therapeutic programs with diverse indications, including cardiovascular and metabolic diseases, inflammation and cancer, severe and rare disorders. Many of the programs are now been developed by leading biopharmaceutical companies, such as AstraZeneca, Biogen Idec, GlaxoSmithKline, Pfizer, Sanofi, Teva, and advanced to phase 2 and phase 3 clinical trials. In January of 2013, an oligonucleotide inhibitor of apolipoprotein B-100 (Mipomersen, Kynamro), discovered and initially developed by Dr. Crooke’s team, was approved by the United States Food and Drug Administration for treatment of familial hypercholesterolemia. Throughout all the years with Ionis Pharmaceuticals, Dr. Crooke also continued contributing to the basics of oligonucleotide science, authoring more than 500 research articles and patents, and editing more than 20 books.

Dr. Crooke received his BS in Pharmacy from Butler University in 1966, PhD and MD at Baylor College of Medicine in 1971 and 1974, correspondingly. Earlier in his career, Dr. Crooke helped create the anticancer program at Bristol-Myers (now Bristol-Myers Squibb), and then led Research and Development at SmithKline Beckman (now GlaxoSmithKline). In 1989, he co-founded Ionis Pharmaceuticals, where he now serves as Executive Chairman and Chief Executive Officer. Dr. Crooke held professor positions at Baylor College of Medicine, University of Pennsylvania Medical School, University of California San Diego, and is currently a Member of the San Diego State University BioScience Center Scientific Advisory Board.

For his contribution to life sciences, Dr. Crooke received a number of awards and honors, including the Lifetime Achievement Award from Scrip, the Director of the Year Award from the Corporate Directors Forum, the Distinguished Scientist Award from the American Chemical Society, the Helix Award for the most important innovation in biotechnology by the Biotechnology Industry Organization, the Ernst and Young Entrepreneur of the Year Award, as well as Distinguished Alumnus at Baylor College of Medicine and at Butler University. In 2006, Nature Publishing Group listed him as decade’s one of the most remarkable and influential personalities in biotechnology.  

 

Additional information about Dr. Crooke can be found in the following sites:

http://www.ionispharma.com/about/management/

http://ir.ionispharma.com/phoenix.zhtml?c=222170&p=irol-govBio&ID=189311

Presentation Title

Antisense Technology: Past, Present, Future

Summary

Antisense technology continues to advance with numerous 2nd generation and beyond antisense drugs in advanced development and quite substantial advances in understanding the molecular events that underlie the mechanisms of action, distribution and side effects. These advances define an exciting potential future for antisense technology and will be discussed.

Mark Edbrooke, PhD

Senior Principal Scientist, Oncology iMed, AstraZeneca, Cambridge, UK

Mark Edbrooke earned his PhD in molecular biology from the University of London. He ran a transnational Gene Interference functional genomics department at GSK that generated target identification and validation data for all therapeutic areas across the company (e.g. oncology, cardiovascular, respiratory, neurology and infectious diseases). He then founded and led a Discovery Performance Unit (DPU) within GSK focused on the development of therapeutic siRNAs and, latterly, on therapeutic antisense oligonucleotides. He recently joined AstraZeneca (AZ) and is involved in AZ’s alliances with Ionis Pharmaceuticals, Regulus Therapeutics, and Moderna Therapeutics.

Presentation Title

Therapeutic nucleic acids including antisense oligonucleotides – significant progress towards a viable drug platform for tackling intractable targets in oncology.

Summary

Recent human clinical data has demonstrated potent activity of systemically-administered, unformulated, antisense oligonucleotides (ASOs) when targeted to liver expressed genes. However, robust activity in extra-hepatic tissues including tumours has been limited with initial ASO chemistries. In contrast, high affinity next generation ASOs have been successfully used to target transcription factors and other intracellular proteins in multiple preclinical cancer models, leading to the translation of these drugs into the clinic. Our experience to date with next generation ASO technology suggest this platform is poised to become a key therapeutic modality to modulate a range of tumour targets intractable to small molecules or antibodies.

Jan GORODKIN, PhD

Professor, University of Copenhagen
Director, Center for Non-Coding RNA in
Technology and Health, Denmark

Jan Gorodkin holds a MSc in physics from the Niels Bohr Institute and obtained his Ph.D. in Bioinformatics from Center for Biological Sequence analysis at the Technical University, Denmark. He did his post docs at Aarhus University, Denmark and Washington University Medical School, St. Louis. He took up positions at the Royal Veterinary and Agricultural University (now University of Copenhagen), and is now professor and head of the bioinformatics group as well as director of Center for non-coding RNA in Technology and Health in the Department of Veterinary Clinical and Animal Sciences. His research interests span from RNA bioinformatics to animal and human genome analysis and his research group has been involved in developing numerous computational tools as well as applying them on genomic and transcription data.

Presentation Title

Computational analysis of RNA structure and interactions in genomic sequence

Summary

A key challenge in computational RNA biology is to search for conserved RNA (secondary) structures, as the conservation of base pairs not necessarily implies conservation in sequence. We have addressed this through a RNA structural alignment strategy followed by a CaptureSeq strategy and structure probing on selected candidates. We also address another key RNA bioinformatics challenge for genome/transcriptome-wide searching of RNA-RNA interactions which is computational expensive. We employ a suffix-array implementation along with a simplified energy model and reach a substantial increase in speed. We, furthermore, use this in an implementation of a siRNA off-target pipeline for which we find inverse relationships between our off-target measure and inhibition efficiencies of siRNAs.

Chuan HE, PhD

Professor, University of Chicago, USA

Howard Hughes Medical Institute

Chuan He is the John T. Wilson Distinguished Service Professor in the Department of Chemistry, Director of the Institute for Biophysical Dynamics at the University of Chicago, and an Investigator of the Howard Hughes Medical Institute. He is also a Cheung Kong Professor and Director of Synthetic Functional Biomolecules Center (SFBC) at Peking University in China. His recent research concerns reversible RNA and DNA methylation in biological regulation. Chuan He’s laboratory has spearheaded development of enabling technologies to study the biology of 5-hydroxymethylcytosine (5hmC) in mammalian genomes. His laboratory also discovered the reversible methylation of N6-methyladenosine (m6A) in human messenger RNA (mRNA) in 2011.

Presentation Title

New sequencing technology to map DNA epigenetic modifications

Summary

Cytosine methylation (5mC) is a well-established epigenetic mechanism essential for genomic imprinting, X chromosome inactivation, silencing of retrotransposons, and lineage-specific expression of many developmental regulatory genes. This epigenetic mark is installed and maintained by DNA methyltransfeases (DNMTs), and has been recently shown to be oxidized to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC) by the Ten-eleven- translocation (TET) family of protein dioxygenases. In humans and mice, 5hmC is found in most cell types and tissues, with the abundance ranging from less than 0.1% to 0.4% of all cytosines. By contrast, the abundance of 5fC and 5caC is very low to non-detectable. We have developed several methods that allow selective detection and sequencing of 5hmC, 5fC, and 5caC with limited genomic materials. Our results indicate genome-wide dynamic methylation/demethylation play critical roles in mammalian gene expression regulation. The presence of 5hmC in promoters, gene bodies, and enhancers of specific loci often associates with gene activation and reflects chromatin state changes. Sensitive detection of 5hmC will therefore offer the best means to interrogate and monitor cell transformation and gene expression changes in future disease diagnosis and prognosis.

Robert Holt, PhD

Professor, University of British Columbia, Canada

Professor, Simon Fraser University, Canada

Scientist, British Columbia Cancer Agency, Canada

 

Rob Holt received his PhD in Pharmacology from the University of Alberta, Canada, in 1998. After a postdoctoral fellowship in molecular evolution at the State University of New York, Dr. Holt joined the company Celera Genomics in Rockville, Maryland where he served on Craig Venter’s team as the Scientific Operations Manager for initial sequencing of the human genome. Since 2003 Dr. Holt has been a Senior Scientist at the British Columbia Cancer Agency (BCCA), where he is Co-director of the BCCA Immunotherapy Program and Co-director of the Genome Canada Science & Technology Innovation Centre. Dr. Holt is recognized for his leadership role in decoding some of the first model organism genomes and pathogen genomes and, more recently, for developing next-generation sequencing methods for interrogating the genetics of the adaptive immune system. He has served as a scientific advisor to the NIH Human Microbiome Project and discoveries by his research group have linked new infectious agents to cancer risk. His current research directions are focused on cancer genomics, T cell engineering, and immune interventions in cancer. He has published over 130 scientific papers that have received >49,000 citations.

Presentation Title

Towards personalized T cell receptor therapeutics: Interrogating the T cell repertoire

Summary

The loci encoding adaptive immune receptors (eg. T cell receptors) have highly unique properties. Stochastic recombination events at these loci during lymphocyte development generate diverse and remarkably personalized immune repertoires that serve to protect self from non-self. With next-generation sequencing methods it is now possible to interrogate immune repertoires at clonotype resolution and obtain a comprehensive view of the adaptive response to immune challenge, including the anti-cancer immune response. However, linking T cell receptors to the specific antigens they recognize remains difficult, and new high-throughput methods will be required to define T cell targets and exploit the full potential of engineered T cell therapeutics.

Jin-Soo KIM, PhD

Professor, Seoul National University
Director ,Center for Genome Engineering, 
Institute for Basic Science and Department of Chemistry, South Korea

– Scientific interests and expertise
  Genome engineering via programmable nucleases including the CRISPR-Cas system
  1) Genome editing in plants, animals, and cultured human cells including iPS/ES cells
  2) Engineered nuclease-mediated gene and cell therapy
  3) Functional genomics using genome-scale libraries of programmable nucleases

– Received degrees (including places and years)
  1987, BS, Dept. of Chemistry, Seoul National University
  1989, MS, Dept. of Chemistry, Seoul National University
  1994, PhD, Dept. of Biochemistry, University of Wisconsin-Madison

– Current position(s) and role(s) in affiliated organizations
  1994-1997, Research Associate, Howard Hughes Medical Institute/MIT
  1997-1999, Principal Investigator, Samsung Biomedical Research Institute
  1999-2005, CEO and CSO, ToolGen, Inc.
  2005-present, Assistant/Associate/Full Professor, Seoul National University
  2014-present, Director, Institute for Basic Science (IBS)
  Home pages: http://cge.ibs.re.kr/html/cge_en and http://gel.snu.ac.kr

Presentation Title

CRISPR RNA-guided Genome Editing in Human Stem Cells, Animals, and Plants

Summary

Genome editing that allows targeted mutagenesis in cells and organisms is broadly useful in biology, biotechnology, and medicine. We have developed ZFNs, TALENs, and Cas9/Cpf1 nucleases to modify chromosomal DNA in a targeted manner. In particular, we used purified Cas9/Cpf1 proteins rather than plasmids to correct large chromosomal inversions in the factor VIII gene that cause hemophilia A in patient-derived iPSCs or to modify diverse genes in animals and plants. The resulting cells and organisms contained small indels at target sites, which are indistinguishable from naturally-occurring variations, possibly bypassing regulatory requirements associated with use of recombinant DNA.
Despite broad interest in RNA-guided genome editing, Cas9 and Cpf1 are limited by off-target mutations. We developed nuclease-digested whole genome sequencing (Digenome-seq) to profile genome-wide specificities of Cas9 and Cpf1 nucleases in an unbiased manner. Digenome-seq captured nuclease cleavage sites at single nucleotide resolution and identified off-target sites at which indels were induced with frequencies below 0.1%. We also showed that these off-target effects could be avoided by using purified Cas9/Cpf1 ribonucleoproteins (RNPs) and modified guide RNAs. Digenome-seq is a robust, sensitive, unbiased, and cost-effective (< USD 1,500) method for profiling genome-wide off-target effects of programmable nucleases.

Troels KOCH, PhD

VP and Head of Research, RNA Therapeutics

Roche, Denmark / Switzerland

Dr. Troels Koch (TK) is Ph.D. in bio-organic chemistry and has worked in the area of nucleic acid chemistry and biology for more than 15 years. TK is co-founder of several Biotech companies of which Exiqon A/S and Santaris Pharma A/S are most commonly known. He is presently Vice President of Research & CTO in Santaris Pharma A/S with main responsibilities to further build on the fundamental understanding of the chemical and biological properties of LNA, refining the LNA antisense drug discovery process, and establishing a drug pipeline on RNA antagonists targeting both mRNA and microRNA. Collectively this work and associated IP has been a driver behind the four major partner deals that Santaris has entered over the past years. During his academic and biotech career TK has gained experience in managing R & D activities, intellectual property, quality systems, regulatory affairs, antisense drug substance/product manufacturing, and nucleic acid bio-organic chemistry. TK is the author of about 70 peer reviewed scientific papers and inventor of about 25 base patents. He is a frequently invited speaker at international conferences, and he has accepted more than 70 invitations in the past decade.

Presentation Title

New perspectives in LNA therapeutics

Summary

A new modelling strategy has been employed to get a better understanding on how the various structural units will impact the properties of LNA. The modelling pointed to the internucleoside phosphorothioate (PS) linkage and demonstrated that stereo defined LNA PS serve as specific determinants for LNA activity. Pre-clinical data will be used to illustrate how stereo defined PS can influence and improve central drug properties of LNA. PS has been a “hot topic” and debated over the years and adding to this the use of stereo defined vs. random mixture PS will be discussed in a bigger picture.

Ekkehard Leberer, Ph.D., Professor of Biochemistry

Senior Director of R&D Alliance Management, Sanofi, Germany

Scientific Managing Director of COMPACT Consortium, Innovative Medicine Initiative, Belgium

Dr. Leberer received his Ph.D. in Biology at the University of Konstanz, Germany (1986). He conducted post-doctoral training in molecular biology at the Banting and Best Institute of the University of Toronto, Canada, and then became a Professor of Biochemistry at the University of Konstanz, Germany (1992). He is currently responsible for R&D Alliance Management at Sanofi, and is the Scientific Managing Director of the Innovative Medicine Initiative COMPACT Consortium on the delivery of biopharmaceuticals across biological barriers and cellular membranes (www.compact-research.org).

Since joining Hoechst Marion Roussel in 1998, Dr. Leberer carried out various managing roles in this company, Sanofi’s predecessor companies and Sanofi itself, including responsibilities in functional genomics, biological sciences and external innovation for oligonucleotide-based therapeutics. He has also served as Head of Biotechnology Germany and a member of the Scientific Review Committee of Aventis Pharma Germany.

Prior to joining pharmaceutical industry, Dr. Leberer served as Senior Research Officer in genetics and genomics at the Biotechnology Research Institute, National Research Council of Canada, Montreal. His research has focused on the molecular mechanisms of signal transduction and the role of signalling molecules in human diseases. He is the principal discoverer of the p21 activated protein kinase (PAK) family of cell signalling proteins and of novel virulence-inducing genes in pathogenic fungi. He is co-author of more than 60 publications in prestigious peer-reviewed journals including Nature and Science.

Presentation Title

MicroRNA therapeutics for targeting the pathways of human disease

Summary

MicroRNAs regulate biochemical pathways and networks of pathways by the mechanism of RNA interference (RNAi). Many microRNAs have been demonstrated to be dysregulated in human diseases. For example, microRNA-21 has been implicated in multiple organs as a microRNA associated with fibrosis and cancer. Therefore, microRNAs open a novel target space for drug development.This presentation will summarize the opportunities and challenges of developing microRNA-based drugs and will illustrate the generation of an anti-fibrotic microRNA-based therapeutic approach by targeting microRNA-21 with an antisense oligonucleotide (anti-miR-21).

Judy LIEBERMAN, MD, PhD

Cellular and Molecular Medicine Program, Boston Children’s Hospital and Department of

Pediatrics, Harvard Medical School, Boston MA USA

Judy Lieberman holds a Chair in Cellular and Molecular Medicine at Boston Children’s Hospital, is Professor of Pediatrics at Harvard Medical School and is Chair of the Executive Committee of Immunology at Harvard Medical School. She earned a Ph.D. in physics from Rockefeller University and worked as a theoretical physicist at the Institute for Advanced Study in Princeton and Fermilab, received an M.D. from Harvard and MIT, did a postdoctoral fellowship in immunology in the Eisen laboratory in the Cancer Center at MIT and worked as a hematologist/oncologist at Tufts Medical Center. She has received numerous awards for her research on AIDS vaccines, immunology and cancer. She is a member of the American Academy of Arts and Sciences.

The Lieberman laboratory has been in the forefront of developing RNAi-based therapeutics and using RNAi for genome-wide screening. They have developed strategies for cell-targeted RNAi to treat viral infection, immune disease and cancer. They also investigate the role of microRNAs in regulating cell differentiation and cancer. The Lieberman laboratory also studies cytotoxic T lymphocytes and their role in immune protection from infection and cancer. They study the molecular pathways used by killer lymphocytes to induce programmed cell death of both mammalian cells and microbes, especially those activated by cytotoxic granule proteases, called granzymes, and immune pore-forming proteins.

Presentation Title

The Silent Treatment: Targeted gene knockdown

Summary

Effective therapeutic strategies for in vivo siRNA delivery to knockdown genesin cells outside the liver are needed to harness RNA interference for treating most diseases. Here we describe two flexible platforms for targeted delivery that use RNA aptamers or antibodies for selective cell uptake in vivo and gene knockdown.

Muthiah MANOHARAN, PhD

Senior Vice President, Drug Discovery, Alnylam Pharmaceuticals, USA
Board Director, Oligonucleotide Therapeutics Society

Dr. Muthiah Manoharan serves as Senior Vice President of Innovation Chemistry at Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA. Dr. Manoharan joined Alnylam in 2003. He built the chemistry group at Alnylam and pioneered the discovery of GalNAc conjugated siRNAs for RNA interference (RNAi) based human therapeutics. He was the former Executive Director of Medicinal Chemistry at Isis Pharmaceuticals, Inc., a leading biotechnology company focused on antisense oligonucleotide-based therapeutics where he had a12-year tenure. With a distinguished career as a world-leading nucleic acid and bioconjugate chemist, Dr. Manoharan is an author of nearly 200 publications and over 300 abstracts, as well as the inventor of over 200 issued U.S. patents. Prior to Isis Pharmaceuticals, He earned his Ph.D. in chemistry at the University of North Carolina-Chapel Hill and conducted post-doctoral work at Yale University and the University of Maryland. He was the recipient of the M. L. Wolfrom award of the ACS Carbohydrate Chemistry Division in 2007.

Presentation Title

RNAi Therapeutics in Human Disease using GalNAc-siRNA Conjugates: How sweet it is to work with sugars

Summary

At Alnylam, siRNA-GalNAc conjugates are emerging as a potential new class of medicine supporting a broad clinical pipeline across multiple therapeutic areas. We have been able to continuously optimize the siRNA chemical modifications and design resulting in the Enhanced Stabilization Chemistry (ESC) platform exhibiting improved efficacy and extended duration lasting for several months. Our progress and applications will be presented.

Craig C. MELLO, PhD

Professor, University of Massachusetts 
Howard Hughes Medical Institute, 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. 

 

Additional information about Dr. Mello can be found in the following sites:

http://www.hhmi.org/scientists/craig-c-mello

http://profiles.umassmed.edu/profiles/ProfileDetails.aspx?From=SE&Person=1009

http://www.nobelprize.org/nobel_prizes/medicine/laureates/2006/mello-bio.html

http://en.wikipedia.org/wiki/Craig_Mello#Awards_and_honors

Presentation Title

RNA-guided inheritance

Summary
Genetic information is passed vertically from parents to offspring. However, new information can also be transferred horizontally from one organism to another. Genomes are filled with evidence for this type of transfer. For example, viral remnants and transposons constitute nearly half of the total DNA in the human genome. In some cases horizontally acquired genes can be functional; mammals express viral glycoprotein homologs, syncytins, that promote membrane fusion essential to the function of the placenta. Similarly, the majority of (formerly) bacterial genes required for mitochondrial function have been transferred into the nuclear genome. My laboratory is interested in how organisms manage and regulate the transfer of genetic information both vertically and horizontally. We have recently discovered that the nematode C. elegans utilizes small-RNA mechanisms related to RNA interference (RNAi) to constantly scan all mRNAs expressed in the germline. Remarkably the animal develops a memory of all expressed (and silenced mRNAs) by transcribing, using a cellular RNA-dependent RNA polymerase, short antisense RNAs from mRNA templates. These ‘memory’ small RNAs are loaded onto Argonaute proteins and are transmitted in the egg and the sperm from one generation to the next. Foreign genes are recognized and silenced because the animal lacks a memory of these non-self mRNAs. The heart of this surveillance mechanism is a highly conserved Argonaute protein (the Piwi Argonaute) and its genomically-encoded small RNA co-factors (piRNAs). The conservation of these factors raises the interesting possibility that other animals including humans employ RNA-guided scanning to distinguish self and non-self genetic information.

Mikiko SIOMI, PhD

Professor, Department of BiologicalSciences, Graduate School of Science,

The University of Tokyo, Japan

Mikiko C. Siomi earned her Ph.D. in Agricultural Chemistry from Kyoto University, Japan in 1994, and then did post-doctoral studies with Prof. Gideon Dreyfuss, HHMI/University of Pennsylvania School of Medicine. Later, Dr. Siomi earned another Ph.D. in Medical Science from the University of Tokushima, Japan in 2003. Dr. Siomi started a joint laboratory with Prof. Haruhiko Siomi in the University of Tokushima, Japan in 1999 for elucidating the function of FMRP and the mechanism of RNAi using the Drosophila system. The laboratory discovered that Ago2 protein, the key player of RNAi, interacts with FMRP, an RNA-binding protein that is encoded by the fmr1 gene, the responsible gene for causing Fragile X Mental Retardation. Later, Dr. Siomi focused on elucidating how RNAi mechanistically occurs and the molecular mechanisms of piRNA biogenesis in the germlines. Dr. Siomi started her own laboratory at the University of Tokyo in 2012 (http://www-siomilab.biochem.s.u-tokyo.ac.jp/index.html). Dr. Siomi co-authored numerous research articles, reviews and book chapters, and currently serves as the president of the RNA Society of Japan and the vice-president of the Molecular Biology Society of Japan.

Presentation Title

PIWI-interacting RNAs in animals

Summary

piRNAs are produced from single-stranded long non-coding RNAs that are transcribed from intergenic piRNA clusters on the genome in the germline. Mature piRNAs are loaded onto PIWI proteins to yield piRISCs and guide the complexes to target RNAs to repress them. piRNAs in the germ cells are then amplified by the ping-pong cycle, in which transposon transcripts are consumed as both the source of piRNAs and the targets of PIWI cleavage, thereby repressing transposons in the cytoplasm. It is becoming clear that piRISCs also mediate transposon silencing in the nucleus in a PIWI cleavage-independent manner. We use two cultured cell lines OSC and BmN4 to understand mechanism(s) underlying the piRNA pathway in animals.

Erik SONTHEIMER, PhD

Professor, RNA Therapeutics Institute

University of Massachusetts Medical School

Worcester, Massachusetts, USA

Erik Sontheimer is Professor in the RNA Therapeutics Institute (RTI) at the University of Massachusetts Medical School. He received his Ph.D. in 1992 from Yale, where he did his thesis work with Joan Steitz on pre-mRNA splicing mechanisms. He was then a Jane Coffin Childs Fund postdoctoral fellow with Joe Piccirilli at the University of Chicago. In 1999, Sontheimer joined the faculty at Northwestern, where he turned his attention to small RNA-based gene regulation in eukaryotes. In 2008 his laboratory also began working on genetic interference in bacteria. Among other advances, they provided the first demonstration that CRISPR RNAs (crRNAs) can target DNA, as well as the first explicit recognition of crRNA’s potential for gene targeting in eukaryotes, pointing the field down the path of RNA-guided genome engineering. He has received an NSF CAREER Award, a New Investigator Award from the Burroughs Wellcome Fund, and the Nestlé Award from the American Society for Microbiology, and he has also been elected to the American Academy of Microbiology. In 2014 he moved to the RTI, where he is continuing his research on the fundamental roles of RNA molecules, and on their uses in biomedical research and medicine. He is a co-founder and Scientific Advisory Board member of Intellia Therapeutics, which is developing Cas9-based genome editing for clinical applications.

Presentation Title

Genetic Interference and Genome Editing by Neisseria meningitidis Cas9

Summary

Cas9 enzymes confer phage immunity in many bacteria and are of great utility in RNA-guided genome engineering. Of the three subtypes of Cas9-based CRISPR systems (TypesII-A, -B and -C), Type II-A Cas9s [e.g. SpyCas9 (1,368 amino acids)] are the best characterized for genome editing. Most Type II-C Cas9 orthologs are considerably smaller (<1,100 amino acids) than SpyCas9, suggesting potential advantages, and our previous work has also defined mechanistic distinctions such as CRISPR RNA (crRNA) processing independence as well as an unusual DNaseH activity. We also adapted NmeCas9 as an effective genome-engineering platform in human pluripotent stem cells and elsewhere. We have since defined the unusually high accuracy of NmeCas9 genome editing, and established unique methods to control its editing activity both temporally and spatially. This presentation will describe these and other recent results.

Jian-Sheng SUN, PhD, HDR

Professor, Muséum National d’Histoire Naturelle

MNHN-CNRS-INSERM, France

Born in Shanghai, after high school, he was sent to France by Chinese government to study theoretical physics. After M.S. degree, he served as assistant professor in the Department of Physics at Fudan University. Later on, he returned to Paris to study nucleic acids, was awarded Ph.D and Habilitation degrees in biophysics at Pierre & Marie Curie University. He also had an entrepreneurial training at HEC business school.

His research in nucleic acids (100+ peer-reviewed publications, 8 patents) led him to co-invent an original concept with Dr. Marie Dutreix at the Institut Curie – “the signal interfering DNA (siDNA)” which jams the recognition and signaling of double strand break (DSB) by using a short dsDNA mimicking a DSB. Acting agnostically at upstream, it can blind DSB repair signaling, thus inhibit all DSB repair pathways causing cancer cell death due to unrepaired DSB, while preserving normal cells.

In 2006, he co-founded DNA Therapeutics, served as Chairman & CEO, managed from scratch to clinical stage this virtually integrated biopharmaceutical company and executed from concept to clinic a 1st-in-class drug development with the help of the experts aggregating skills in early stage drug development, CMC, regulatory affairs and business development. After demonstrating good safety and significant antitumor activity of the 1st– in-class siDNA drug candidate in a phase I/IIa trial in patients with cutaneous metastatic melanoma (presented at the ASCO 2015), the Company was acquired in early 2016 by Onxeo – a public company specializing in the development of innovative oncology therapeutics. After closing, he is back to MNHN, focusing his research on the interplay between DNA damage, cancer and aging.

Prof. Sun received the physical chemistry 1991 award by French Chemical Society, the joint Grand Prize of Life Science 2006 by French Senate, INSERM-Transfert and ESSEC, the Award of Best Innovative Entrepreneur in Health 2008 by French Business Angels investing in health, the Next Gem award of best biotech at Biovision Investor Conference 2013.

Presentation Title

Signal interfering DNA (siDNA): from an original concept to a promising a first-in-class DNA repair inhibitor against advanced stage cancer in patients

Summary

Enhanced DNA repair activity in advanced stage cancers confers resistance to treatment. The inhibition of DNA repair makes resistant cancers vulnerable to the cytotoxic effects of chemotherapy and radiotherapy, can restore their efficacy. However, as a major cell survival mechanism in all living kingdoms, DNA repair is made of specialized and redundant pathways. Therefore, the inhibition of DNA repair by a classic single target inhibitor is inefficient, except in the case of concomitant genetic defects in alternative pathways (i.e. BRCA mutations for PARP inhibitors).

Signal interfering DNA (siDNA) is a novel approach to fully inhibit DNA repair activities, as siDNA jams the recognition and the signaling of the most lethal DNA damage – double strand break (DSB), by using a synthetic short double strand DNA fragment mimicking a DSB lesion. Acting agonistically at upstream of all DSB repair pathways, siDNA can blind DSB signaling that disorganizes DSB repair system and thereby inhibits all DSB repair pathways. Genetic instability and other characteristics of cancer cells make them highly sensitive to the consequence of siDNA-induced DSB repair inhibition as compared to normal cells, and thus provide good safety and high therapeutic index.

This presentation will describe the mechanism of action, preclinical and clinical proofs of concept of siDNA jointly studied by DNA Therapeutics and the team led by Dr. Dutreix at the Institut Curie.

Elizabeth TRAN, PhD

Associate Professor

Purdue University, USA

Elizabeth Tran earned her PhD in biochemistry at North Carolina State University where she developed an in vitro assembly and methylation system for trans acting box C/D snoRNAs. She then pursued postdoctoral training in the laboratory of Dr. Susan Wente at Vanderbilt University, where she identified the role of the RNA helicase Dbp5 in nuclear mRNA export. She joined the faculty at Purdue University in 2009, where she explores the biochemical mechanism and biological function of DEAD-box RNA helicases, a class of enzymes that are required for all aspects of RNA metabolism but whose in vivo roles are yet to be identified. Her laboratory is most well known for studies of the DEAD-box RNA helicase Dbp2 in S. cerevisiae and insights into the roles of long non-coding RNAs (lncRNAs) in gene expression. These insights span the fields of RNA biology, epigenetics, and metabolism. Moreover, the scientific community has highlighted her work for pivotal, paradigm shifting advances in lncRNA biology (Best of JBC 2012, Nature highlight, Science Signaling highlight). Her long-term goal is to understand the connection between RNA structure, gene regulation, and cellular adaptation in relationship to organismal survival and human pathology. In addition to research, Dr. Tran is a strong supporter of the international scientific community and mentoring the next generation of scientists. She is currently serving a two year term as a Director on the Board of the RNA Society, an international organization with ~1000 members worldwide.

Presentation Title

Long Non-Coding RNAs Regulate Gene Expression Through Formation Of RNA-DNA Hybrids

Summary

 

Long non-coding (lnc)RNAs, once dismissed as a products of spurious transcription, have now emerged as biochemically diverse regulators of the eukaryotic transcriptome. By virtue of technological advances in sequencing, current studies estimate the number of lncRNAs in mammals to be ~50,000-90,000. However functional characterization of individual lncRNAs has lagged behind. Studies using the budding yeast Saccharomyces cerevisiae, an organism that relies heavily on lncRNAs following evolutionary loss of the microRNA pathway, have provided unprecedented insight and paradigms for gene regulatory mechanisms. Using this model system to define the roles of individual lncRNAs, we found that the galactose (GAL) genecluster-associated lncRNAs promote transcriptional induction through formation of lncRNA-DNA hybrids or R-loops. Formation of these structures is regulated by the evolutionarily conserved RNA helicase Dbp2, whose cellular localization is regulated in response to environmental cues that stimulate induction. The GAL lncRNAs promote displacement of the Cyc8 corepressor and subsequent gene looping, a role that provides a competitive fitness advantage to yeast cells by promoting a faster response to the presence of galactose in the media over yeast cells lacking the GAL lncRNAs. RNA-seq of the DBP2-dependent transcriptome reveals that this enzyme plays a widespread role in regulation of the metabolic gene network. Because the GAL lncRNAs promote faster transcriptional induction without impacting the final steady-state transcript levels, we predict that regulated lncR-loop formation is a widely used mechanism to control the timing of transcriptional switches necessary for adaptation, growth and development.

Ada YONATH, PhD

Professor, Weizmann Institute of Science, Israel

Nobel Prize in Chemistry 2009

Ada Yonath is focusing on protein biosynthesis, on antibiotics hampering it, on pathogenic parasites and on the origin of life. She graduated from the Hebrew University, Jerusalem, and postdocted at Carnegie-Mellon and MIT (USA). In the seventies she joined the Weizmann Institute and established the first structural-biology laboratory in Israel. During 1986-2004 she also headed Max-Planck-Research-Unit for Ribosome Structure in Hamburg. Among others, she is a member of US-National-Academy-of-Sciences; Israel Academy; German Science Academy (Leopoldina); the Pontificia Accademia-delle-Scienze (Vatican). She holds honorary doctorates from the universities of Oslo, NYU, Mount-Sinai, Oxford, Cambridge, Hamburg, Berlin-Technical, Patras, De-La-Salle, Xiamen, Lodz, Strasbiurg. Her awards include the Israel Prize; Louisa-Gross-Horwitz Prize; Linus-Pauling Gold Medal; Wolf-Prize; UNESCO/L’Oreal Award; Albert-Einstein-World-Award for Excellence; Nobel Prize for Chemistry.

Presentation Title

Combating resistance to antibacterial and anti-parasite ribosomal antibiotics?

Summary

Resistance to antibacterial and anti-parasitic agents alongside the spread of non-degradable antibiotics metabolites are severe problems in contemporary medicine and ecology. Recent structures of ribosomes from multi-resistant pathogens and from a eukaryotic parasite identified features that can account for species-specific diversity in infectious-diseases susceptibility. These structural features may lead to design of environmental-friendly degradable drugs, which will also be species-specific antibiotics-drugs, thus, reducing resistance while protecting the environment and preserving the microbiome.

Yi-Tao YU, PhD

Professor, University of Rochester School of Medicine and Dentistry, USA

Yi-Tao Yu received his PhD degree in Molecular Biology from Case Western Reserve University in 1994. He was awarded a post-doctoral fellowship from the Damon Runyon Cancer Research Foundation, and did his post-doctoral work (RNA biology) with Joan Steitz at Yale University (HHMI) from 1995 to 1999. He then joined the faculty of the Department of Biochemistry and Biophysics at the University of Rochester in late 1999. He is currently also a member of the Center for RNA Biology and Chair of the RNA Structure and Function Cluster at the University of Rochester. Dr. Yu’s research interests are in the areas of RNA modification, snRNP biogenesis and pre-mRNA splicing. Over the years, he has generated numerous publications and made significant contributions in these areas.

Presentation Title

RNA-guided RNA Modifications

Summary

 

Pseudouridylation and 2’-O-methylation are the most abundant modifications found in RNAs. These modifications are catalyzed largely by RNA-guided mechanisms. By changing the guide sequences within the guide RNA, we can re-direct modifications to new sites. With regard to function, our work indicates that modifications can profoundly alter the chemical properties of an RNA, thus influencing the contributions of the RNA to cellular process in which it participates.

       论坛起源于广州核酸国际论坛,在政府及各界支持下已经连续举办了五届,历届大会报告人汇集诺贝尔奖得主在内的全球顶级科学家、学者和企业家,论坛聚焦精准医学、生命科学、基因治疗、核酸药开发等最新热点进展,分享来自全球范围内核酸研究及应用的重大成果和进展。中国核酸国际论坛(CNAF)的知名度与影响力也受到国际学术界与企业界的高度赞誉,被誉为中国核酸研究与产业化的重要风向标。