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Friday, February 5

NOVEL FORMULATIONS FOR RNAi DELIVERY

8:30 AM Chairperson’s Opening Remarks

Bob D. Brown, Ph.D., Senior Vice President, Research, Dicerna Pharmaceuticals, Corp.

8:35 Therapeutic siRNA Delivery: Tackling the 800 Pound Gorilla

Steven F. Dowdy, Ph.D., Investigator, Howard Hughes Medical Institute; Professor, Department of Cellular & Molecular Medicine, University of California, San Diego School of Medicine

To date, 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 all cell types assayed (primary and tumorigenic) in a non-cytotoxic fashion.  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.  These observations demonstrate the ability of PTD-DRBD to efficiently delivery siRNAs in vivo.

9:05 Induction of Therapeutic Gene Silencing in Leukocyte-Implicated Diseases by Targeted and Stabilized Nanoparticles

Dan Peer, Ph.D., Head, Laboratory of Nanomedicine, Department of Cell Research and Immunology and the Center for Nanoscience and Nanotechnology, Tel Aviv University

Leukocytes are among the most difficult cells to transduce with RNAi. We developed a strategy that can target different subsets of leukocytes and selectively silence genes in vivo using targeted, stabilized nanoparticles (tsNPs). These carriers do not induce lymphocyte activation, interferon responses or release liver enzymes and are fully degradable. Three pre-clinical examples inflammatory bowel disease (IBD), blood cancer and viral infection will be discussed. We will show that tsNPs can be used for in vivo validation of new drug targets, for prevention of viral infection and for inducing therapeutic gene silencing in a preclinical setting.

9:35 Characterization of Immune Responses to tkRNAi Therapeutics

Johannes Fruehauf, M.D., Ph.D., VP, Research, Cequent Pharmaceuticals, Inc.

Transkingdom RNA interference (tkRNAi) describes a novel method for delivery of therapeutic RNA interference into gastrointestinal tissues using engineered bacteria which produce and deliver mediators of RNAi. Clinical trials are about to begin for the prevention of colon Polyposis, and for the treatment of Inflammatory Bowel Disease (IBD). Here we demonstrate recent results from large screening efforts characterizing the effects of tkRNAi on cytokine profiles and innate immunity.

10:05 Sponsored Presentation (Sponsorship Opportunity Available)

10:20 Coffee Break

11:00 Panel: Do We Understand the Challenges We Face With RNAi Therapeutics?

Panelists:

Bob D. Brown, Ph.D., Senior Vice President, Research, Dicerna Pharmaceuticals Corp.

Ian MacLachlan, Ph.D., CSO, Tekmira Pharmaceuticals

John Rossi, Ph.D., Professor and Chair, Molecular Biology, Beckman Research Institute of the City of Hope

Steven Highlander, Ph.D., Partner, Intellectual Property, Fulbright & Jaworski, L.L.P.

12:00 PM Luncheon Presentation (Sponsorship Opportunity Available) or Lunch on Your Own

NOVEL APPROACHES FOR TARGETED DELIVERY

1:00 Chairperson’s Remarks

John Rossi, Ph.D., Professor and Chair, Molecular Biology, Beckman Research Institute of the City of Hope

1:05 In vivo delivery of Dicer substrate RNAs for treatment of HIV infection

John Rossi, Ph.D., Professor and Chair, Molecular Biology, Beckman Research Institute of the City of Hope

The application of RNAi for treatment of HIV infection has many advantages over conventional drugs. The inhibitors can be rapidly changed according to the viruses ability to mutate.  This presentation will discuss the use of aptamers and dendrimers to deliver Dicer substrate RNAs in vivo.  The results obtained demonstrate that Dicer substrate siRNAs can be delivered in a cell type specific manner with an aptamer, and can be generally delivered with dendrimers to effectively inhibit HIV replication in a humanized mouse model.

1:35 Targeted RNA-based Cancer Therapies

Paloma H. Giangrande, Ph.D., Assistant Professor, Department of Internal Medicine, University of Iowa

A major hurdle for the clinical translation of siRNAs into effective therapies is delivery. We describe an RNA aptamer-based approach for the targeted delivery of siRNAs to prostate cancer (PC) cells. The aptamer-siRNA reagent (chimera) is effective when administered systemically and is suitable for efficient chemical synthesis. When administered systemically to mice bearing PSMA-positive tumors, the RNA chimera triggered tumor regression without affecting normal tissues. This work is the first description of in vivo efficacy following systemic administration of an aptamer-siRNA chimera and thus represents a milestone for this platform technology.

2:05 Development of Novel Therapeutic RNAi Compounds and Effective in vivo Delivery Approaches

Joanne Kamens, Ph.D., Senior Director of Research Collaboration Management, RXi Pharmaceuticals 

RNA interference (RNAi) offers a novel approach to the drug development process, because RNAi compounds can potentially be designed to target any one of the genes in the human genome. Other potential advantages of RNAi therapeutics include, rapid development of lead compounds, high selectivity for the target gene, high potency (low dose) and low toxicity due to natural mechanism of action. We will introduce unique single-oligo (rxRNAsolo) and short-duplex (rxRNAnano) RNAi compounds, as well as novel in vivo delivery approaches, including self-delivering rxRNA molecules (sd-rxRNA) for local and systemic delivery, and targeted delivery to phagocytic immune cells using.

2:35 Talk Title to be Announced

C. Satishchandran, Ph.D., Chief Technology Officer, Research Technology Center, Pfizer, Inc.

3:05 Close of Conference