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4th RNAi Research & Therapeutics Conference

  March 06, 2013  
GTCbio, San Francisco, CA

Day 1 - Thursday, May 9, 2013
7:00Continental Breakfast & Registration
7:55Welcome & Opening Remarks
Session I: Emerging Field: Non-Coding RNA Discovery
9:10Tentative Manipulating Non-coding RNAs for Therapeutics
 Mark A. Kay, MD, Ph.D., Dennis Farrey Family Professor, Stanford University
9:35Iain Fraser, Ph.D., Chief, Signaling System Unit, NIH
10:00Morning Networking & Coffee Break
10:40Small Noncoding RNA Therapies for HIV-1
 John Burnett, Assistant Research Professor, City of Hope
Session II: RNA and Diseases
12:05Lunch on Your Own
2:00Nuclear Function of Argonautes and miRNA in Cancer Cells
 Long-Cheng Li, MD, Associate Professor in Residence, University of California, San Francisco
Session III: Target Discovery and Validation
2:25Michael T. McManus, Ph.D., Principal Investigator, University of California, San Francisco
3:00Patrick Paddison, Assistant Member, University of Washington
3:35Afternoon Networking & Coffee Break
4:15Pieter R. Cullis, Ph.D., FRSC, Professor, University of British Columbia
5:05Oral Presentations from Exemplary Submitted Abstracts
 To be considered for an oral presentation, please submit an abstract here by May 20, 2013. Selected presentations will be based on quality of abstract and availability. Presentation slots fill up fast so please submit your abstract ASAP.
5:35Networking Reception

Day 1Day 2
Day 2 - Friday, May 10, 2013
7:00Continental Breakfast & Registration
Session IV: RNA Delivery Methods
9:10Single siRNA Nanocapsules for Enhanced RNAi
 Ming Yan, Ph.D. , Assistant Researcher, University of California, Los Angeles
9:35Targeted Image-Guided RNA (TIGR) Therapies
 Paloma H. Giangrande, Ph.D., Assistant Professor, University of Iowa
 Recent clinical trials of small interfering RNAs (siRNAs) have highlighted the need for robust delivery techniques that will enable the application of this therapeutic to increasingly to humans. Cell conjugation of siRNAs to cell-specific ligands provides a viable solution to this problem. Synthetic RNA ligands (aptamers) represent an emerging class of pharmaceuticals with great potential for targeted therapeutic/diagnostic applications. While encouraging, the extended use of RNA aptamers as a delivery tool for siRNAs awaits the identification of RNA aptamer sequences capable of targeting and entering the cytoplasm of many different cell types. We describe novel selection methodologies for the rapid identification and characterization of RNA aptamers capable of delivering siRNAs into the cytoplasm of target cells. We coupled these methodologies with state-of-the-art RNA chemistries and fluorescent technologies resulting in effective, targeted image-guided RNA (TIGR) reagents that can be easily tracked in vivo. Importantly, these TIGRs may represent a crucial first step in the transition of siRNAs from the bench-side into the clinic.

• Platform technology for identifying cell-targeting RNA ligands
• Targeted delivery technology for RNAi
• Methodologies for assessing delivery of siRNAs to cells
• Tracking RNAi in vivo
10:00Morning Networking & Coffee Break
10:40Anita Seto, Research Scientist, miRagen Therapeutics
11:05RNA Aptamers as Tools for Specific Cancer Cells Targeting and Delivery
 Vittorio de Franciscis, Ph.D., Research Director, National Research Council, Italy
 Endogenous miRNAs, have been shown to regulate complex intracellular pathways including survival, proliferation and migration thus acting as oncogenes or oncosuppressors. However, the lack of safe and reliable means for specific delivery actually represents a major obstacle to their development as therapeutics. In this respect, nucleic acid aptamers are promising carriers for the specific delivery of therapeutics to targeted cells. Using the anti-Axl aptamer, GL21.T, here we addressed the generation of aptamer/miRNA conjugates as bifunctional molecules that combine the receptor-inhibiting function of the aptamer moiety with the silencing function of miRNAs. We conjugated a member of the let-7 family, let-7g, to GL21.T and show that in the resulting chimera, the let-7g cargo is specifically delivered to target cells and enters into the Dicer processing machinery thus leading to high and specific silencing activity with reduced miRNA intracellular expression. The oncosuppressive function of such conjugates is selective and receptor-mediated both in vitro and in vivo, thus showing that the aptamer mediated delivery of miRNA may be an effective tool to target cancer genes in a cell specific manner.

• Development of Aptamers as ligands for cancer cell-surface targeting 
• Design of bifunctional aptamer-miRNA conjugates
• Methodology for cell-specific intracellular delivery of microRNAs and anti-miRs
11:30DPC Technology for siRNA Delivery: Moving from Platform to Pipeline
 David Lewis, Ph.D., Vice President, Arrowhead
 We have developed a platform technology for systemic siRNA delivery called Dynamic Polyconjugate (DPC). A key feature of DPC technology is a reversibly-masked, membrane-active polymer whose activity is revealed only in the acidic environment within endosomes. Interestingly, we have found that simple co-injection of hepatocyte-targeted DPC polymer and a liver-tropic, cholesterol-conjugated siRNA (chol-siRNA) results in highly effective target gene knockdown in both rodents and non-human primates at low chol-siRNA doses. This is accomplished without complex formation or interaction of the DPC polymer and the chol-siRNA prior to reaching the target cell.
Currently, we are developing this DPC technology for the treatment of chronic hepatitis B virus (HBV) infection. The use of RNAi therapeutics for the treatment of HBV is attractive as it enables knock down of viral RNAs, including the pre-genomic RNA from which the replicative intermediates are derived, thus reducing both the viral load and the viral proteins that result in disease and negatively impact the immune system’s ability to eliminate the virus. We have found that a single i.v. co-injection of hepatocyte-targeted and fully biodegradable DPC (NAG-MLP) with chol-siRNAs targeting conserved human HBV sequences resulted in profound repression of viral RNA and multi-log knockdown of viral proteins and DNA with long duration of effect in mouse models of chronic HBV infection. This therapeutic approach holds great promise for patients chronically infected with HBV.

Attendees will learn about:
Novel nucleic acid delivery platform
Targeted siRNA delivery
Mechanism of endosomal escape
RNAi therapeutic for HBV
12:05Lunch Provided by GTC
Session V: Therapeutic, Diagnostic and Clinical Applications
1:35Miravirsen an Oligonucleotide Directed Against miR-122 for the Treatment of HCV Infection
 Michael Hodges, MD, Chief Medical Officer, Santaris
 Hepatitis C virus (HCV) is a major cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma and is the leading indication for liver transplantation in the United States and Europe. The World Health Organization (WHO) estimates that 180 million people (3% of the World’s population) are infected with HCV.
Miravirsen sodium is a ?-D-oxy-Locked Nucleic Acid (LNA) modified phosphorothioate anti-sense oligonucleotide inhibitor of the liver-expressed microRNA-122 (miR-122). miR-122 binds to two target sites (S1 and S2) in the 5’UTR of the HCV genome, and forms an oligomeric miR-122-HCV complex, thereby protecting the 5’ HCV genome from nucleolytic degradation. Thus, miravirsen will reduce HCV RNA levels indirectly by targeting the critical host factor miR-122.
In clinical trials in healthy volunteers and patients with HCV, miravirsen was safe and well tolerated when given by weekly subcutaneous injection over 29 days (five injections) at doses up to 7 mg/kg. No dose limiting toxicities were identified.
In a four-week monotherapy trial, SPC3649-203, in subjects with chronic GT1 HCV infection, the mean reduction in HCV RNA for the 3, 5 and 7 mg/kg dose groups (five weekly doses over 29 days) was approximately 1, 2 and 3 log10, respectively. The observed decline in HCV RNA was sustained well after the last dose of miravirsen. The reduction in group mean HCV RNA levels was correlated to miravirsen dose level and group mean plasma exposure (trough and peak). There was no evidence of genotypic resistance.
2:00Towards Clinical Translation of siRNA-based STAT3 Targeting in Cancer
 Hua Yu, Ph.D., Associate Chair and Professor, Beckman Research Institute at City of Hope Comprehensive Cancer Center
 The reality is that social networking has enabled and encouraged the patients' voice, whether as an individual with a diagnosis or collectively through established vehicles such as change.org. Patients with rare conditions feels isolated and alone, they, by definition, have to become their own advocate, or if unable based on age or other circumstances, a family member assumes the role. They will need to educate themselves about the diagnosis and its implications, seek out medical expertise, educate their family and extended family and most likely connect with individuals with the same diagnosis wherever and whenever they can. Including patients, understanding the collective wisdom if the disease community, involving them in discussions will result in partnerships intended to de-risk and accelerate the drug development process.
2:25Elena Feinstein, MD, Ph.D., Chief Scientific Officer, Quark Pharmaceuticals
3:00Harnessing the miRNA Biogenesis Pathway for Novel Therapeutic Applications
 Marco Weinberg, Senior Research Scientist, The Scripps Research Institute
3:25HumanizedMmice for in vivo Testing of Novel RNAi and Aptamer Therapeutics
 Ramesh Akkina, Ph.D., Professor of Virology, Colorado State University
3:50Conference Concludes
Organized by: GTC
Invited Speakers:
Ramesh Akkina, Ph.D.
Professor of Virology
Colorado State University
John Burnett
Assistant Research Professor, Department of Molecular and Cellular Biology
City of Hope
Chang-Zheng Chen
Assistant Professor, Microbiology & Immunology
Stanford University
Trinna Cuellar
Researcher, Molecular Biology
Pieter R. Cullis, Ph.D., FRSC
Professor, Biochemistry and Molecular Biology
University of British Columbia
Elena Feinstein, MD, Ph.D.
Chief Scientific Officer 
Quark Pharmaceuticals
Vittorio de Franciscis, Ph.D.
Research Director, Institute of Endocrinology and Experimental Oncology
National Research Council, Italy
Iain Fraser, Ph.D.
Chief, Signaling Systems Unit, Laboratory of Systems Biology
National Institutes of Health
Paloma H. Giangrande, Ph.D.
Assistant Professor, Hematology, Oncology and Blood & Marrow Transplantation Faculty
University of Iowa
Michael Hodges, MD
Chief Medical Officer
Mark Kay, MD, Ph.D.
Professor, Pediatrics & Genetics
Stanford University
David Lewis, Ph.D.
Vice President, Biology
Long-Cheng Li, MD
Associate Professor in Residence, Department of Urology
University of California, San Francisco
Michael T. McManus, Ph.D. 
Assistant Professor, Department of Microbiology & Immunology
University of California, San Francisco
Patrick Paddison Ph.D. 
Assistant Member, Human Biology
Fred Hutchinson Cancer Research Center
Anita Seto 
Research Scientist
miRagen Therapeutics
Marco Weinberg
Senior Research Scientist
The Scripps Research Institute
MIng Yan, Ph.D. 
Assistant Researcher, Department of Microbiology, Immunology & Molecular Genetics
University of California, Los Angeles
Hua Yu, Ph.D.
Associate Chair and Professor, Cancer Immunotherapeutics & Tumor Immunology
Beckman Research Institute at City of Hope Comprehensive Cancer Center
Deadline for Abstracts: 2012-04-30
Registration: Please visit conference website to register. Discount Available.
E-mail: infogtcbio@gtcbio.com
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