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MONDAY, JUNE 8
7:30 am – 6:00 pm Registration Open
7:30 am Morning Coffee
8:30 Chairperson’s Remarks
C. Satishchandran, Ph.D., Chief Technology Officer, Research Technology Center, Pfizer Inc.
8:45 Delivering RNAi Therapeutics Using Chemistry
Muthiah Manoharan, Ph.D., Vice President, Drug Discovery, Alnylam Pharmaceuticals, Inc.
9:15 Systemic Delivery Against Multiple Liver Targets Using a DiLA2-Based Liposome
Roger Adami, Ph.D., Associate Director, Molecular Pharmaceutics, MDRNA Inc.
A novel class of modified amino acids has been developed for in vivo systemic delivery of siRNA. In vivo data using a DiLA2 based liposome and proprietary Dicer siRNAs demonstrating efficacy in the reduction of three liver targets; ApoB, DGAT2, and PCSK9, and the prevention of tumor growth in an orthotopic bladder cancer model will be presented.
9:45 Anti-HIV Aptamer Mediated Delivery of siRNAs to HIV Infected Cells
John Rossi, Ph.D., Professor and Chair, Molecular Biology, Beckman Research Institute of the City of Hope
Dual inhibitory function anti-gp120 aptamer-siRNA chimeras have been developed in which both the aptamer and the siRNA portions have potent anti-HIV activities. This siRNA delivery system is specifically internalized into cells expressing gp160 and once internalized functional siRNAs are generated via Dicer processing of the siRNAs from the chimeric aptamer-siRNA constructs, resulting in RNAi mediated knockdown of target gene expression. The aptamer-siRNA chimeras strongly suppressed HIV-1 infection in a RAG-hu mouse model infected with HIV.
10:15 Coffee Break
10:45 Peptide Transduction Domain Delivery of siRNAs
Steven F. Dowdy, Ph.D., Investigator, Howard Hughes Medical Institute and Professor, Department of Cellular & Molecular Medicine, University of California- San Diego, School of Medicine
siRNA delivery remains the rate-limiting step for RNAi therapeutics development. We developed a Peptide Transduction Domain-dsRNA Binding Domain (PTD-DRBD) fusion protein siRNA delivery approach. PTD-DRBD delivered siRNAs induced RNAi responses in the entire population of 30+ primary and transformed cell types in a non-cytotoxic fashion, including HUVECs, T cells and hESC. PTD-DRBD combinatorial in vivo delivery of EGFR and Akt2 siRNAs induced a synthetic lethal response that significantly increased survival of intracerebral glioblastoma pre-clinical models. Taken together, these observations demonstrate the ability of PTD-DRBD to efficiently deliver siRNAs in vitro and in vivo.
11:15 Therapeutic AtuRNAi in the Pulmonary Vascular Endothelium Protects from Vascular Hyperpermeability
Ansgar Santel, Ph.D., Senior Scientist, Silence Therapeutics AG
The AtuPLEX technology, a liposomal formulation of stabilized siRNA molecules (AtuRNAi), can be used systemically for RNAi-mediated therapeutic application in the vascular endothelium. The vascular endothelial cells contribute to the pathophysiology of many diseases. Here, we will discuss our approach of using a cationic liposomal formulation of siRNA molecules systemically for RNAi in the pulmonary vasculature. We characterized the involvement of particular target genes in the progression of vascular permeability in different murine models and analyzed their loss-of-function effect on improved vascular barrier function in vivo.
11:45 Panel Discussion: RNAi Delivery: What Is the Progress and Where Are We Lacking?
12:15 pm Close of Morning of Session
12:30 pm Presentation 1 (Opportunity Available)
1:00 pm Presentation 2 (Opportunity Available) or Lunch on Your Own
2:00 Chairperson’s Remarks
2:05 Pre-Clinical Development of siRNA Delivery in Cancer Therapy
Leiming Li, Ph.D., Associate Research Investigator, Cancer Research, Abbott Laboratories
The major hurdle for siRNA therapeutic is to deliver siRNA to the desired sites, and the solid tumor posts even a higher hurdle because of its anatomy. We have attacked the problem through varieties of routes and investigated several critical aspects of siRNA therapy for cancer. We will discuss the lessons learned in the pre-clinical development of siRNA therapeutics and our evaluation of different delivery systems on the market.
2:35 Targeting T Cells for RNAi-Based HIV Therapy
Priti Kumar, Ph.D., Assistant Professor, Department of Internal Medicine/Section for Infectious Diseases, Yale University
Therapeutic application of siRNA requires delivery to the appropriate subcellular compartment, within the target cell, within the target tissue responsible for the pathology. The potency of RNAi as an HIV therapeutic has been largely restricted to in vitro demonstrations due to problems of siRNA delivery to the relevant HIV-infected immune cells in vivo. Novel antibody-based approaches for targeted delivery of antiviral siRNA into human T cells will be discussed.
3:05 Developing Immune Targeting Nanoparticles Containing siRNAs to Curtail Inflammatory Bowel Diseases
Dan Peer, Ph.D., Head, Laboratory of Nanomedicine, Department of Cell Research & Immunology, and the Center for Nanoscience and Nanotechnology, Tel Aviv University
We developed a strategy to target gut leukocytes and selectively silence genes in leukocytes in vivo using targeted, stabilized nanoparticles. This study revealed Cyclin D1 to be a potential anti-inflammatory target, and suggests that the application of similar modes of targeting by siRNA may be feasible in other therapeutic settings.
3:35 Sponsored Presentation (Opportunity Available)
3:50 Refreshment Break
4:15 Targeted RNA Therapies for the Treatment of Prostate Cancer
Paloma H. Giangrande, Ph.D., Assistant Professor, Department of Internal Medicine, University of Iowa
The first generation aptamer-siRNA chimera can deliver siRNAs targeting cell-survival genes to PSMA-expressing cancer cells in vitro and in vivo. Here, we describe the development of chimeras with enhanced in vitro silencing activity and specificity over the first generation chimera. In addition, these ‘optimized’ chimeras have been truncated to enable chemical synthesis for scale-up production. Importantly, when administered systemically to mice bearing PSMA-positive tumors, the ‘optimal’ chimera resulted in pronounced tumor regression.
4:45 Dynamics of siRNA Glomerular Filtration and Proximal Tubule Handling in Vivo Using 2-Photon Microscopy
Bruce A. Molitoris, M.D., Director, Division of Nephrology and Professor of Medicine, Indiana University
Following intravenous injection Cy-3 labeled siRNA was rapidly filtered across the glomerulus and taken up selectively by proximal tubule cells. Total cellular and cytosolic accumulation in proximal tubule cells was quantified using threshold analysis and revealed a maximum at 120 minutes with a rapid decay over the next four hours. The biological activity of the siRNA correlated closely to the fluorescent half life.
5:15 Welcoming Reception in the Exhibit Hall
6:30 End of Day