RNA in DRUG DEVELOPMENT - RNA as a Tool and TargetNovember 6 - 8, 2002 • Wyndham Emerald Plaza • San Diego, CA USA [ Overview | Agenda | Call for Posters | Register ] View Electronic Brochure (PDF)OverviewWith exciting developments in RNA therapeutics research emerging every day, it is vital to examine the interaction of RNA with other small molecules. To rationally design new classes of RNA based drugs it is critical to learn about different mechanisms to alter gene expression as well as how RNA can be used either as a target or a tool to achieve this goal. This 2nd international conference will address these key issues along with strategies for RNA based drugs to successfully integrate into the marketplace. Join the international group of experts on RNA to discuss the latest on: - Aptamers Take advantage of this unique opportunity to hear the state-of-the-art on RNA - therapeutics from leaders in industry and academia. Register today - space is limited AgendaWednesday, November 6, 2002 - Pre-Conference Workshop:Opportunities and Challenges in Commercializing RNA in Drug Development 12:15 Registration, Coffee and Refreshments 12:55 Chairperson's Opening Remarks 1:00 From Bench to Business: Bottlenecks in Starting a Biotechnology Company There a number of terrific discoveries made every day at the bench but converting this basic research to a commercial opportunity presents many challenges to the investigator. First and foremost, how do you build a company, hire a management team and scientists without cash. Without the team, you will be "too early" to attract financing but without the financing, you can't build a team. Then there's the ip, everyone needs it but the patent office is overburdened and the response is slow. Without the issued ip your "barrier to entry and ability to operate is uncertain". Once these barriers are overcome and financing is obtained, it is time to recruit the team, competing against better funded and "more stable" companies. Finally, everything is in place and you're ready to ... start the next round of financing. 1:40 Clinical Research: Challenges and Requirements Abstract not available at time of print. 2:20 Refreshment Break 3:10 Successfully Launching a Company in the RNA Field The RNA field has captured the interest of several entrepreneurs and investors, but launching a company successfully can pose many challenges. This talk will parallel PTC's successful fund-raising and growth with the strategy that made it possible, highlighting the challenges managed by the leadership of PTC and sharing lessons learned along the way. 3:50 Emerging Investment Opportunities in RNA Technologies The emerging area of RNA as a tool and target for drug development has led to a wealth of opportunities. The investment potential of this area will be discussed. Additional topics will include what makes a technology attractive from an investors' perspective, evaluating scientific business proposals, as well as common mistakes made by first time entrepreneurs. 4:45 End of Workshop Thursday, November 7, 20028:00 Registration, Poster / Exhibit Set-Up, Coffee and Pastries RNAi8:50 Chairperson's Opening Remarks 9:00 RNAi: Silencing Gene Expression in Adult Mice RNAi has been demonstrated to be an effective tool in silencing gene expression in lower organisms and in mammalian cells. Data will be presented to demonstrate the utility of this platform in silencing gene expression in adult mice. The use of siRNA will be compared to that of long dsRNA for both the duration and magnitude of the silencing effect. 9:35 High Throughput RNAi As a Tool in Drug Discovery Abstract not available at time of print. 10:10 Small Synthetic Double-Stranded RNAs (SIRPLEX) as the Basis for the Development of Novel Therapeutics We demonstrated in a mouse model system that chemically synthesized small interfering RNA duplexes (SIRPLEX) are capable of mediating RNA interference in living adult mammals. In transgenic mice expressing the green fluorescent protein (GFP) in all organs and tissues, the repetitive intravenous injection of chemically unmodified SIRPLEX without any carriers or conjugates caused a substantial decrease in the level of GFP expression in several organs. Presently, clinically relevant tumor mouse models (malignant melanoma, pancreatic carcinoma) are being treated with SIRPLEXES directed against tumor-related targets. Preliminary results are very promising. 10:45 Refreshment Break and Poster / Exhibit Viewing 11:15 Subcellular Localization of siRNA Directed Against Experimental and Therapeutic Targets We have developed several expression cassettes where small, structured RNAs are synthesized by RNA polymerase III and localized to different subcellular compartments. Effective suppression of target gene product levels is achieved by nuclear expression of a hairpin RNA transcript containing both strands of siRNA-like duplexes, but not by cytoplasmic expression. Versions of nuclear-targeted siRNA appear to be most effective and are being tested against cellular and viral targets. 11:50 siRNA: Target Validation and Beyond Abstract not available at time of print. 12:25 siRNA: Design, Synthesis and Applications in Gene Silencing High-throughput-solutions for up to date siRNA design, reliable siRNA synthesis, siRNA analytics, siRNA transfection and analysis of silencing effects will be presented. Several examples and an outlook where the siRNA technology might develop itself into will be given. 1:00 Luncheon, Sponsored by The Knowledge Foundation, Inc. 2:25 Chairperson's Remarks Ribozymes2:30 Selection of a Novel Ribozyme Through Phase I Trials of Herzyme - an anti-Her2 Ribozyme This talk will cover how a novel ribozyme, predisposed to function in physiological conditions, was identified and developed into a potential therapeutic agent. The research done to optimize the nuclease resistance, minimize the size and cost of production, demonstrate biological activity, assess the pharmacokinetics, and show localization in target tissue will be covered. 3:05 Libraries of Allosterically Regulated RNA Lassosª for Specific Inhibition of Gene Expression We describe novel agents for gene inhibition that have certain advantages over ordinary antisense, ribozyme and RNAi approaches. Allosterically regulated RNA Lassos hybridize to and become topologically linked with complementary RNA targets, creating complexes that effectively block translation. Effective lasso inhibitors can be efficiently derived from specially prepared libraries containing only sequences represented within a defined set of targets. 3:40 Refreshment Break and Poster / Exhibit Viewing Aptamers4:10 Photoaptamer Arrays for Proteomic Analysis Photoaptamer-based assays are in development for candidate proteins, and are being integrated into a single, multiplexed array to allow for the simultaneous measurement of proteins of interest. The SomaLogic arrays will have value for basic researchers interested in protein quantification in a variety of biological systems. Beyond basic research, the arrays should be of value to pharmaceutical and biotech companies during clinical trials - patient stratification and drug toxicity might be followed with proteomic arrays. 4:45 Developing RNA Aptamers for Therapeutic Applications We have employed SELEX to isolate high affinity, 2'flouro-modified RNA aptamers to a variety of clinically relevant target proteins including Angiopoietin 2, CTLA4 and coagulation Factor IXa. Each of these aptamers can block the activity of their target protein in vitro and impede the target proteinÕs activity in vivo. The ANG2 aptamer can inhibit angiogenesis in the rat corneal pocket angiogenesis model, the CTLA4 aptamer can enhance the potency of tumor vaccines in mice, and the Factor IXa aptamer can anticoagulate pigs. Results from these various animal studies will be presented. Collectively they demonstrate that aptamers can be utilized to modulate the activity of a variety of clinically important target proteins in vivo. 5:20 Spiegelmers-A Novel Substance Class for Therapeutic Applications By exploiting the principle of reciprocal chiral substrate specificity together with an in vitro selection process, NoxxonÕs proprietary platform technology allows the design of enantiomeric L-oligonucleotides. These so-called spiegelmers (German: Spiegel=mirror) show high affinity and specificity for their target molecules and are insensitive to enzymatic degradation in biological fluids. In vitro and in vivo data will be presented for L-oligonucleotide ligands to a variety of targets indicating the potential of spiegelmers as a new class of oligonucleotide-based therapeutics. 6:05 End of Day One Friday, November 8, 20028:15 Poster / Exhibit Viewing and Coffee and Pastries RNA as A Tool8:50 Chairperson's Remarks 9:00 Group II Introns as Controllable Gene Targeting Vectors (Targetrons) Group II introns are site-specific retroelements that use a novel mobility mechanism in which the excised intron RNA inserts directly into a double-stranded DNA target site and is then reverse transcribed by the intron-encoded protein. Because the DNA target site is recognized primarily by base pairing of the intron RNA, it is possible to control the target specificity of intron insertion simply by modifying the intron RNA. The introns have been used to develop a new type of gene targeting vector (targetron) for highly efficient genetic manipulation of both gram-negative and gram-positive bacteria, and experiments are in progress to apply the technology to mammalian cells. 9:35 Evolved Nucleic Acid Sensors and Therapeutics In vitro evolution from random sequence libraries makes it possible to build nucleic acids that specifically recognize and bind to virtually any kind of target, such as ions, metabolites, drugs, toxins, peptides and proteins. Aptamers, the nucleic acid equivalent to antibodies, possess numerous advantages that make them preferred candidates for drug development. Furthermore, combining molecular recognition with ribozyme activity allows us to engineer effector-dependent RNA/DNA enzymes for use as biosensors in a wide range of in vitro and in vivo applications. Catalytic activity can be easily detected in a variety of formats, including FRET, FP, SPR, real-time PCR, SPA and microarrays, and serves as a quantitative measure for analyte concentration. Latest advances in aptamer and riboreporter technology will be presented. 10:10 Structure-Based Discovery of Novel Inhibitors of the 50S Ribosomal Subunit The X-ray crystal structures of the 50S ribosomal subunit and its complexes with a number of classes of antibiotics have been determined in a several academic labs and at Rib-X Pharmaceuticals, Inc. This structural data fuels the closed-loop drug discovery approach at Rib-X, which integrates novel computational chemistry tools and library design techniques with chemical synthesis and biochemical and microbiological analysis in the pursuit of new compounds useful as antiinfective agents. This approach has yielded recently a novel series of compounds that show promise against major resistance mechanisms in streptococci, enterococci, and staphylococci. 10:45 Refreshment Break and Poster / Exhibit Viewing 11:15 Rapid Conversion of Functional Proteomics Data into Small Molecule Lead Compounds NascaCell follows a highly efficient strategy for target validation and interconnected small molecule lead compound identification. Functional nucleic acids, so-called ÒNucleic Acid BiotoolsÓ (NABs) are used to inactivate endogenous proteins within their physiological context. Thus, our technology not only enables us to validate the role of individual proteins in the etiology of disease, but simultaneously gives rise to NAB-lead structures with crucial features of a final drug: specific binding and functional inactivation of target proteins. By exploiting the information stored in the NAB-lead structure, small molecule lead compounds can subsequently be identified by competitive HTS assays using universally applicable fluorescence-based systems. 11:50 Ribonomics: Interrogation of Functional Clusters for Drug Discovery The molecular analysis of diseased tissue by transcriptomic and proteomic technologies has generated enormous amounts of raw data creating a new, unintended bottleneck in the drug discovery process. The prioritization of the vast number of potential targets identified through these technologies has proven tedious and inefficient Ñ at this point, the "high-throughput" nature of such research is lost. At Ribonomics, we accelerate the target discovery and validation process by interrogating the cell's own organizational scheme through characterization of the functional clustering of RNA molecules. Functional clusters of mRNAs and regulatory RNA binding proteins are a rich and novel source of therapeutic and diagnostic targets for the management of human disease. 12:25 Lunch On Your Own 1:55 Chairperson's Remarks RNA - Delivery2:00 Peptide-Mediated RNA Delivery mRNA-based transfection offers several advantages over DNA in slowly-dividing or non-cycling cells for use in gene therapy, stemming mainly from its cytoplasmic site of expression that obviates the necessity for nuclear entry. We have studied the key requirements of synthetic vectors enabling efficient mRNA expression in order to design better-defined and more versatile vectors for delivery of RNA. Our results on the development of effective peptide-based RNA delivery systems will be discussed. *In collaboration with: Thierry Bettinger1, Robert C. Carlisle2, Manfred Ogris3, David Oupicky4 and Leonard W. Seymou2, Bracco Research, Switzerland1, University of Oxford, UK2, Ludwig-Maximilians-Universitat Munchen, Germany3, Detroit, USA4 RNA as Target2:35 Nonsense Suppression: An Approach to Treating Genetic Disorders with Small Molecules Many diseases occur as a consequence of mutations in an individual's DNA. A common type of mutation (occurring in 15-30% of all inherited diseases) leads to the synthesis of an mRNA containing an inappropriate stop codon (nonsense codon) within its protein coding region. The occurrence of such a premature stop codon arrests translation at the site of early termination and results in the synthesis of a truncated protein. Nonsense mutations are significant causes of numerous well-characterized inherited diseases, including cystic fibrosis, hemophilia, familial hypercholesterolemia, retinitis pigmentosa, and Duchenne's muscular dystrophy. Patients harboring such nonsense mutations produce only one percent, or less, of the pertinent functional protein. Boosting expression to only five percent of normal levels can greatly reduce the severity and/or even completely alleviate disease symptomology. Dr. Welch will describe a drug discovery program that has successfully produced animal data in treating nonsense suppression as well as discuss the plans for further therapeutic usage. 3:10 Targeting mRNA - A New Approach to Address Old Targets Current drug therapy is based around only about 500 molecular targets, mainly cell membrane receptors and enzymes. Genomics has revealed many new candidate drug targets, and high-throughput screening has greatly enhanced the chance to get new lead compounds for these targets. This approach is successful, but there are also valuable drug targets for which no good lead compounds have been found. Targeting these genes at the mRNA level is an attractive new approach to reassess these well established targets, as it builds on the biological knowledge gathered over many years. Ultimately, targeting mRNA even allows genes of which the biochemical function is unknown (ESTs) to enter into the drug discovery process. 3:45 Targeting RNA: Fluorescence and NMR Techniques to Identify Novel Therapeutics RNA-based drug discovery requires general approaches for detecting and quantifying RNA-protein interactions that can be used as high-throughput screens and for obtaining rapid structural information to guide rational drug design. I will present our combined fluorescence and NMR approach that has allowed identification of compounds which specifically interact with the RRE stem-loop IIB from HIV-1 and inhibit Rev peptide interaction. Call for PostersCall for Posters Size of Posterboard: 3x4 feet (90 x 120 cm) Note: If you are submitting a poster, you MUST be registered and paid in advance to ensure that a posterboard is reserved for you.
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