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WEDNESDAY, NOVEMBER 4
7:30 am Continental Breakfast Breakout Discussions
8:35 Chairperson’s Remarks
Bob D. Brown, Ph.D., Senior Vice President, Research, Dicerna Pharmaceuticals Corp.
8:40 Reversal of Drug Resistance in Cancer: Dual Sequential Treatment with Targeted si/shRNA and Drug Packaged Nanocells
Himanshu Brahmbhatt, Ph.D., Joint Chief Executive Officer and Director, Cancer Therapeutics, EnGeneIC Pty. Ltd.
We demonstrate in vitro and in vivo results showing dramatic reversal of drug resistance and effective treatment of such tumors via a dual treatment approach with siRNA- followed by drug-packaged, bi-specific antibody-targeted nanocells. Case studies in dogs with late-stage relapsed cancers show rapid tumor regression and disease stabilization. Detailed toxicology and immune response studies show absence of toxicity/immunogenicity despite the dogs receiving over 20 doses of the minicell-based therapeutics.
9:10Use of siRNA for Amelioration of Aseptic Lung Inflammatory Conditions
Elena Feinstein, M.D., Ph.D., Chief Scientific Officer, Quark Pharmaceuticals, Inc.
We have used siRNAs targeting a number of genes in mouse models of aseptic lung inflammation, i.e. LPS instillation or ischemia-reperfusion injury. siRNA was delivered by inhalation, intratracheal or intranasal instillation. Efficacy of siRNAs was monitored by counting inflammatory cells and measuring protein concentration in broncho-alveolar lavage fluid and by functional assays.
9:40 Pre-clinical and Clincial Development of Atu027, (siRNA-lipoplex/AtuPLEX), for Oncology
Klaus Giese, Ph.D., Chief Scientific Officer, Silence Therapeutics plc
Atu027 refers to a liposomally formulated siRNA targeting PKN3 expression in the vascular endothelium. Preclinical studies in rodents and non-human primates demonstrated that intravenous administration is well tolerated and gives rise to RNAi-mediated suppression of PKN3 gene expression. Various proof-of-concept experiments on mouse tumor xenografts suggest profound inhibition of tumor progression and particularly of metastasis, which laid the foundation for therapeutic application in oncology. Atu027 is currently tested in a Phase-I clinical trial on subjects with advanced solid cancers. Pre-clinical data emphasizing pharmacological activity in mouse models and an update on the current Phase-I study will be discussed.
10:10 Networking Coffee Break in the Exhibit Hall
10:55 Development of Novel RNAi Therapeutic Compounds and In Vivo Delivery Approaches
Dmitry Samarsky, Ph.D., V.P. , Technology Development, 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 and low toxicity due to natural mechanism of action. Effective delivery of synthetic compounds is critical for the successful use of RNAi as a therapeutic. We will describe novel RNAi delivery approaches (including oral delivery to macrophages) potentially suitable for therapeutic applications.
11:25 Keynote Presentation
RNAi: Developing A New Therapeutic Platform
John M. Maraganore, Ph.D., Chief Executive Officer, Alnylam Pharmaceuticals
RNAi offers a possible platform on which to identify potential picomolar active drug candidates to any target, including those that are otherwise ‘undruggable’ or not amenable to conventional drugs, such as small molecule, protein, or monoclonal antibody therapeutics. Unique to the RNAi product engine is the sheer speed at which lead molecules can be identified. Despite the promise, challenges remain, including delivery hurdles and the clear demonstration of efficacy in well-controlled human clinical study, in order to translate the therapeutic potential of RNAi into clinical reality.
11:55 Panel Discussion: Addressing the Clinical Challenges Associated with RNAi Therapeutics
12:25 pm Luncheon Presentation (Sponsorship Opportunity Available) or Lunch on Your Own
1:55 Chairperson’s Remarks
Dmitry Samarsky, Ph.D., V.P. , Technology Development, RXi Pharmaceuticals
2:00 siRNA Construct and Delivery for Effective RNAi
Michael V. Templin, Vice President, Discovery Research and Pharmaceutical Development, MDRNA, Inc.
MDRNA’s approach combines potent siRNA constructs and efficient delivery. siRNAs contain non-nucleotide monomers with high in vivo activity and improved profiles. Delivery involves a Di-Alkylated Amino Acid (DiLA2)-based liposome platform. Matching construct and delivery to the gene and therapeutic indication maximizes RNAi, while minimizing the potential for undesired effects.
2:30 Novel Cationic Liposome Formulation for RNAi-based Validation of Therapeutic Targets in Rheumatoid Arthritis
Florence Apparailly, Ph.D., Senior Scientist, INSERM U844
We aimed at evaluating the potential of RNA interference (RNAi)-based gene therapies in experimental models of rheumatoid arthritis (RA). We have developed an innovative cationic liposome formulation to target macrophages and demonstrated that weekly intravenous administration of siRNAs targeting pro-inflammatory signalling cascades efficiently decreased disease severity and restored immunological balance in collagen-induced arthritic mice. This work reveals novel potential drug development targets.
3:00 Networking Ice Cream Refreshment Break in Exhibit Hall (Last Chance for Viewing)
3:40 siRNA-Based Topical Microbicides Targeting Sexually Transmitted Diseases
Deborah Palliser, Ph.D., Assistant Professor, Albert Einstein College of Medicine
Sexually transmitted diseases (STD), such as HSV-2 infect 20% of people in the U.S. and cause significant morbidity. There is no cure for HSV-2 and STDs are also cofactors for HIV transmission. We have used siRNAs specific for HSV-2 virus and host cellular receptors to assess whether siRNAs could be used as a component in a microbicide that targets HSV-2 and here I will present our findings.
4:10 Nuclear Gene Silencing with U1 Adaptor Oligonucleotides
Sam Gunderson, Ph.D., Associate Professor, Department of Molecular Biology and Biochemistry, Rutgers University
We have developed a novel gene silencing method called U1 Adaptor that uses single stranded oligonucleotides to inhibit polyadenylation in the nucleus in a gene specific fashion. Without a polyA tail the pre-mRNA is degraded leading to a reduction in mature mRNA for that gene. The method is potent (subnanomolar IC50), as specific as siRNA and can be used alone or synergistically with other gene silencing methods. Improvements in U1 Adaptor design will be presented that indicate how they will aid emerging oligonucleotide-based therapies.
4:40 Locked Nucleic Acid-based Oligonucleotides (LNA-ONs) as RNA Antagonists for the Control of Cancer
Lee Greenberger, Ph.D., Vice President, Research, Enzon Pharmaceuticals, Inc.
We are exploring the use of the latest generation of antisense single-stranded molecules using LNA-based technology to down-regulate key targets in cancer that are not easily druggable with antibodies or small molecules. LNA-ONs have been identified to hypoxia inducible factor -1alpha (HIF-1alpha), survivin, androgen receptor, beta-catenin, PI3KCA, and human epidermal growth factor receptor-3 (HER3). Compounds show specific and marked down-regulation of the target and anti-tumor effects in vitro and in animal models. The first two compounds are currently in clinical trials; updates will be provided.
5:10 Close of Conference
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