RNA in Drug Development - RNA as a tool and a target

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Overview

The RNA in Drug Development conference will take place as scheduled.

Our deepest sympathy's go out to the people involved in the widespread tragedy of Tuesday, September 11, 2001. There are no words to describe the senselessness of this horrible act. Our thoughts are with the families at this time.

Sincerely,
Craig Wohlers
President

Recent advances in RNA splicing, gene regulation and RNA metabolism has led to greater insight into the use of RNA as a tool and target for drug development. In addition, the realization that RNA performs a wide range of structural and functional activities independent of its role as carrier of genetic information has led to a growing interest in using RNA for the design of new classes of therapeutics.

Discover new insights as leading scientists from around the world discuss the challenges and new technologies used in the research of RNA aimed at finding more efficient targets for drug design.

- RNA interference
- Ribozyme mediated repair of mutant DNA and RNA
- Ribozyme mediated targeting of HIV RNA
- GeneBloc Technology
- Small Molecule Modulation of protein / RNA interaction
- RNA targeted bioactive ligands
- Ligand based drug discovery strategy
- Escort Aptamers as Tissue Targeting Agents
- Spiegelmers
- Intramers
- Aptabalance Biosensors
- RNA/DNA reporter engineering: in vitro and in vivo application
- Efficient Synthesis of RNA Oligonucleotides

Don't miss this unique opportunity to learn the latest in RNA drug development. Register today!

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Agenda

New update as of August 10th!

Monday, November 12, 2001

9:00 Chairperson's Opening Remarks
Bruce A. Sullenger, Ph.D., Center for Genetic and Cellular Therapies, Departments of Surgery and Genetics, Duke University Medical Center

RNAi

9:05 Target Validation and Functional Genomics Employing Gene Silencing Technology
C. Satishchandran, CSO, Nucleonics, Inc.
Functional genomics rely on the ability to inactivate target genes to assign gene function. Currently, targeted gene inactivation in single cells is achieved by homologous recombination, antisense and ribozyme based technologies. Double-stranded RNA mediated gene silencing offers a unique, effective and rapid approach to sequence specific gene inactivation, both in tissue culture and adult animals. Unlike other technologies gene silencing is systemic. Strategies employing RNAi for target validation in cells and animals and novel library-based approaches have been developed and will be discussed.

9:40 Small Interfering RNAs and Their Activity in Mammalian Cells
Thomas Tuschl, Ph.D., Department of Cellular Biochemistry, Max Planck Institute for Biophysical Chemistry, Gottingen, Germany
RNA interference (RNAi) is the process of sequence-specific, post-transcriptional gene silencing in animals and plants, initiated by double-stranded RNA (dsRNA) homologous in sequence to the silenced gene. The mediators of sequence-specific mRNA degradation are 21- and 22-nt small interfering RNAs (siRNAs) generated by RNase III cleavage from longer dsRNAs. These 21-nt siRNA duplexes specifically suppress expression of endogenous and heterologous genes in different mammalian cell lines, including human embryonic kidney (293) and HeLa cells. Therefore, 21-nt siRNA duplexes provide a new tool for studying gene function in mammalian cells and might eventually be used as gene-specific therapeutics.

10:15 Applications of RNAi in Mammalian Systems
Kathleen M. Murphy, Benitec Australia Ltd., Australia*
RNAi offers considerable potential as both an experimental and practical tool in biotechnology. We have been using DNA constructs to inactivate gene expression in animal cells with constructs designed to initiate RNAi. We have targeted a variety of important animal genes for inactivation and have also explored the possibility of generating viral resistant cell lines using this technique.
*In collaboration with: , R.R. Rice, P. Sedlak, E. O'Brien, A. Kassianos, N. Maugeri, B. Harrison, A. Muirhead, K.C. Reed and M.W. Graham, Benitec Australia Ltd., Australia

10:50 Refreshment Break and Exhibit/ Poster Viewing

Aptamers / Spiegelmers

11:15 Escort Aptamers for Diagnostic Imaging and Therapy
Brian Hicke, Senior Research Scientist, Gilead Sciences
Many are aptamers designed to block protein function. We describe a new class of ligands, escort aptamers, that operate instead as tissue-targeting agents. One such "escort aptamer" is an effective tumor imaging agent in mouse, and now requires clinical assessment. Escort aptamers have further potential for therapeutic delivery of radionuclides or chemotherapeutic molecules.

11:50 Aptamers and Antidotes: A Novel Approach to Drug Design
Christopher P. Rusconi, Assistant Research Professor, Dept. of Surgery, Duke University Medical Center*
There is a significant clinical need for effective anti-thrombotic agents with improved safety profiles. To this end, we have generated potent aptamer antagonists of coagulation factor IXa (FIXa), the best of which has a sub-nM Ki and is able to completely inhibit FIXa activity in human plasma. Furthermore, this aptamer is a potent anticoagulant in vivo as it is capable of systemically anti-coagulating a pig following IV bolus injection. Current efforts are aimed at improving the in vivo duration of this aptamer's anticoagulant effect, and evaluating the ability of the aptamer to block pathologic thrombosis in rodent artery damage models.
*In collaboration with: Rebekah White1, Juliana Layzer1, Elizabeth Scardino1, Michael Milton1, Jeffrey H. Lawson1, Dougald Monroe2 and Bruce A. Sullenger1, Duke University Medical Center, Durham1, University of North Carolina, Chapel Hill2

12:25 Spiegelmers - A Novel Concept for Oligonucleotide-Based Therapeutics
Dr. Sven Klussmann, CSO, Noxxon Pharma AG, Germany
Over the last years, tremendous progress has been made in the field of oligonucleotide-based therapeutics. However, their utility for therapeutic applications is limited due to their susceptibility to nucleases present in biological fluids.
Noxxon's proprietary spiegelmer technology allows us to circumvent this limitation using mirror-image L-DNA or L-RNA aptamers (spiegelmers). The principles of reciprocal chiral substrate specificity coupled to the in vitro selection process make it possible to generate L-oligonucleotide ligands that are exceptionally stable in vivo. The spiegelmer approach has been used to identify mirror-image oligonucleotide ligands for a variety of targets and their efficacy has been shown in vitro as well as in vivo.

1:00 Luncheon sponsored by PTC Therapeutics
RNA-Targeted Small Molecules
Stuart Peltz, Ph.D., President and CEO, PTC Therapeutics
This presentation will highlight the importance of RNA as a target and a tool for drug discovery with an overview of the company's present research in RNA-targeted small molecules.

RNA as tool for drug discovery

2:25 Chairperson's Remarks
Petra Burgstaller, Ph.D., Senior Research Scientist, Noxxon Pharma AG, Germany

2:30 Aptabalance Biosensor
Beate Schmid, Ph.D., Senior Research Scientist, Center for Advanced European Studies and Research, Caesar Foundation, Germany
Biosensors take advantage of the high selectivity and sensitivity of molecular recognition processes of biological macromolecules and combine it with a physical transducer. We exploit the ability of aptamers to bind their cognate ligand with high specificity and affinity and combine this with a mass sensitive transducer, a so called quartz crystal microbalance. The specific interaction between analyte and aptamer results in an increase in mass which can directly be detected and converted into an electrical signal.

3:05 Spliceosome Mediated RNA Trans-Splicing (SMaRT TM); A Platform Technology for Reprograming Genes at the mRNA Level.
Lloyd G. Mitchell, MD, CSO, Intronn LLC
Intronn is pioneering the development of SMaRT, a new method for rewriting the 5', 3' or middle exon(s) of a gene by invading the splicing of any chosen pre-mRNA and inserting any desired gene sequence in vitro or in vivo. The advantages of SMaRT include reducing the size of the delivered gene, acquisition of the regulation of the target gene, and adding new levels of specificity to any gene delivery method. The applications of SMaRT include gene therapy, gene repair, engineering better and safer plants, imaging gene expression, genomics, and target validation.

3:40 Intramers - Novel Tools for Functional Proteomics
Dr. Michael Blind, Director of Research, NascaCell GmbH, Germany
The development of automated in vitro selection allows routine isolation of aptamers that can be used as inhibitors to validate the function of almost any given protein. Intracellular aptamers (intramers) demonstrate the impressive potential of characterizing proteins by specific nucleic acid inhibitors inside living cells. Besides elucidating a protein's role in cellular and disease-relevant pathways, the information stored in the intramer can be used in developing techniques to identify pharmaceutical lead compounds.

4:15 Refreshment Break and Exhibit / Poster Viewing

4:45 GeneBloc Technology to Unravel Signaling Pathways
Klaus Giese, Ph.D., Vice President Research, atugen AG, Germany
atugen has developed a technology platform to create new classes of therapeutics with increased selectivity and efficacy and reduced side effects based on our unique ability to elucidate gene function and its role in disease. Data will be presented showing the unraveling of specific signaling pathways with the goal to identify novel intervention points for therapeutic treatment.

5:20 Ribozyme Reporters as Tools for Drug Discovery
Charles Wilson, VP Technology, Archemix, Inc.
In the search for novel therapeutics, much effort has been directed towards high throughput technologies for monitoring gene expression and the response of cells to test compounds. Allosterically activated RNA/DNA enzymes can be evolved in vitro to recognize target ligands with high affinity and specificity. By tightly controlling conditions for ribozyme evolution, reporters that distinguish small molecules differing by a single atom or variant isoforms of the same protein ligand can be generated. Catalytic activities can be easily detected by optical and other methods. As such, these molecules have a wide range of potential applications in proteomic analysis and drug discovery. This presentation will outline recent advances in RNA/DNA reporter engineering and the development of both in vitro and in vivo applications.

5:55 Modified Nucleosides: Understanding the RNA Target, Improving the Nucleic Acid Therapeutic or RNA Tool
Paul F. Agris, Ph.D. Professor, Department of Molecular and Structural Biochemistry, North Carolina State University, Raleigh, NC, and Chief Scientific Officer, Neos Discovery, Inc.

Approximately 100 modified nucleosides occur in RNAs and a considerable number of non-natural analogues have been synthesized. These modifications provide chemistries and structures that aid in understanding the structure/function relationship of the target RNA at the point of intervention. Additionally, the modified nucleoside properties can be used to enhance the binding activities of antisense tools or therapeutics. Modifications are similar to those of amino acids in that they are charged, polar, or hydrophobic (aliphatic or aromatic). For investigation of structure/function relationships, we have adapted phosphoramidite RNA synthesis for the incorporation of many natural and non-natural modifications into tRNA.

6:30 End of Day One

Tuesday, November 13, 2001

8:15 Coffee and Pastries

Ribozymes

9:05 Making Ribozymes Work in Cells
John Rossi, Professor of Molecular Biology, Director, Department of Molecular Biology, Dean, Graduate School of Biological Sciences, Beckman Research Institute of the City of Hope, Duarte, CA
My talk will cover various approaches we have developed to identify ribozyme cleavage sites on native RNAs, methods for expressing ribozymes from viral vector backbones, and approaches used to co-localize ribozymes and target RNAs in cells. I will describe ribozyme mediated targeting of HIV RNAs and summarize clinical trial results, as well as describe experiments with ribozymes that downregulate cellular transcripts encoding biologically important or therapeutically relevant targets.

9:40 Ribozyme Drugs for the Treatment of Proliferative Disease
Joan M. Robbins, Ph.D., Senior Director, Product Development, Immusol, Inc.
Immusol has refined combinatorial ribozyme library technology to deliver over 10 million unique ribozymes to identify therapeutic drug targets in a process called Inverse Genomicsª. The resulting targets can be used to screen for small molecule or antibody drugs. The ribozymes themselves can be used directly as drugs. A chimeric ribozyme drug has been developed that targets Proliferating Cell Nuclear Antigen, a key cell cycle control element. This drug is under evaluation for the treatment of several conditions resulting from excessive proliferation.

10:15 Refreshment Break and Exhibit / Poster Viewing

10:45 Repair of Genetic Instructions by Ribozymes
Bruce A. Sullenger, Ph.D., Center for Genetic and Cellular Therapies, Departments of Surgery and Genetics, Duke University Medical Center
Much effort has been expended attempting to develop gene therapy based treatments for many inherited and infectious diseases. Progress toward this end has been hampered by an inability to transfer genes into cells and have their expression regulated properly. Recently we began to develop a fundamentally different approach to gene therapy that is based upon ribozyme-mediated repair of mutant RNA and DNA. Toward this end, we have recently demonstrated that trans-splicing group I ribozymes can perform RNA cleavage and ligation reactions upon sickle ß-globin and mutant p53 encoding transcripts and in the process convert these mutant RNAs into mRNAs encoding either wild type globin or p53 transcripts inside cells. More recently in collaboration with Alan Lambowitz's laboratory, we have employed mobile group II introns to modify DNA sequences via reverse splicing. Our results from these and related experiments will be discussed.

11:20 Clinical Development of Synthetic Ribozymes
Nassim Usman, Vice President, Research & Development, Ribozyme Pharmaceuticals
The down-regulation of gene expression using ribozymes represents a novel approach for the treatment of disease. Chemically modified ribozymes have been developed that are resistant to nucleases yet retain catalytic activity. Four ribozymes of this class of molecules; one targeting the VEGF receptor flt-1 mRNA, ANGIOZYME(tm); one targeting the 5'-UTR of HCV, HEPTAZYME(tm); one targeting her2 mRNA, HERZYME(tm); and one targeting HBV mRNA, HepBzyme(tm), are currently in clinical development, ranging from preclinical through Phase II efficacy studies. Data from these programs to date have demonstrated that treatment with synthetic stabilized ribozymes results in efficacy in several preclinical models, are well tolerated in animal and human studies, and can be administered by daily SC bolus injection.

12:05 Lunch on your own

1:25 Chairperson's Remarks
John Rossi, Professor of Molecular Biology, Director, Department of Molecular Biology, Dean, Graduate School of Biological Sciences, Beckman Research Institute of the City of Hope, Duarte, CA

RNA - targeted drugs

1:30 Drugs That Target the Ribosome
Joseph D. Puglisi, Associate Professor, Department of Structural Biology, Director, Stanford Magnetic Resonance Laboratory, Stanford University School of Medicine, Stanford
Aminoglycosides are the paradigm for RNA-directed therapeutics. They target functional sites on the 30S ribosomal subunit, and cause a decrease in translational fidelity. Aminoglycosides distort the structure of the decoding site of the 30S subunit, allowing non-cognate tRNAs to be selected. We will give on overview of our work on these antibiotics, and the insights it has provided into ribosome mechanism.

2:05 NMR and Fluorescence screens for RNA Targets
James R. Williamson, Ph.D, Professor, Department of Molecular Biology and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA
The tools of structural biology can be adapted to develop screening strategies for identification of RNA binding ligands. In our laboratory, we have been studying the structure and assembly pathway of the 30S ribosomal subunit. Based on these studies we have developed fluorescence screens that will permit identification of RNA binding ligands that are potential inhibitors of ribosome assembly. We have also adapted NMR affinity-based screens to identify RNA binding ligands to structured RNAs as lead compounds. These advances in methodology are collateral benefits from our structural biology efforts on RNA structure and RNA-protein interactions.

2:40 Small Molecule Modulation of Protein/RNA Interactions
Tony Giordano, Vice President, Research, Message Pharmaceuticals, Inc.
Message Pharmaceuticals has developed a proprietary platform technology with unprecedented flexibility to discover new classes of drugs aimed at modulating protein/RNA interactions. Screening programs for seven gene targets are in various stages of development at Message. These targets and the disease associated with them are: TNF-( (arthritis/inflammation); Rev/RRE (HIV/AIDS); Her2 (breast cancer); RNaseP (resistant bacteria); APP (Alzheimer's Disease); uPAR (metastatic cancer); and EPO (anemia associated with chronic renal failure). Active molecules have been identified in the first five of these programs and will be discussed.

3:15 Ligand Design for RNA Targets
Thomas Hermann, Computational Chemistry & Structure, ANADYS Pharmaceuticals, Inc.
The development of drugs that target specifically RNA folds opens exciting new ways to expand greatly the existing repertoire of protein-targeted therapeutics. The rapidly growing knowledge of RNA three-dimensional structure and interaction with small molecules enables rational approaches to develop RNA-targeted bioactive ligands.

3:50 Refreshment Break and Exhibit / Poster Viewing

4:15 Ligand-Based Drug Discovery Against RNA Using Mass Spectrometry
Richard H. Griffey, VP Research, Ibis Therapeutics*
Structured RNAs have recently emerged as an exciting new
target for small molecule therapeutics. Conventional HTS
discovery strategies measuring disruption of RNA-protein interactions have proven less successful. We describe a ligand-based drug discovery strategy that addresses the inherent difficulties with RNA targets. The strategy is based on: 1) using a mass spectrometry (MS)-based assay to measure the affinity of chemical motifs for a target; 2) performing competitive binding experiments and molecular modeling with the motifs to determine the binding site(s) of the ligands; 3) fusing binding motifs into a more complex structure to afford higher affinity compounds; 4) identifying the appropriate linker group using MS. Examples of applying this strategy to identify new classes of lead molecules for ribosomal RNA targets will be presented.
*In collaboration with: S.A. Hofstadler, K. Lowery, J. Drader, E. A. Jefferson, Y. Ding, M. Migawa, K. Sprankle, V. Mohan, S. Osgood, and E.E. Swayze, Isis Pharmaceuticals

4:50 The Efficient, High Yield Synthesis of RNA Oligonucleotides via Novel 5'-O-Silyl-2'-O-Orthoester Chemistry
Stephen Scaringe, Ph.D., Chief Scientific Officer, Dharmacon Research, Inc.
The chemical synthesis of RNA oligonucleotides is a
valuable resource for biological research. A new approach
for RNA synthesis will be presented describing the use of 5'-O-silyl ether and acid-labile 2'-orthoester protecting groups. RNA synthesis proceeds efficiently on commercial synthesizers in high yields. Analysis by anion exchange HPLC shows the quality and yields of RNA synthesized with this chemistry is unprecedented. Furthermore, the technology enables analysis and purification of stable 2'-O-protected RNA. This property serves to minimize possibilities for degradation of the RNA. In addition, it now possible to analyze troublesome sequences, which, when fully 2'-O-deprotected, do not easily resolve into one major conformation due to strong secondary structure. When ready for use, the RNA is easily 2'-O-deprotected in mild-acidic aqueous buffers in 30 minutes. This new RNA chemistry has enabled the routine high quality synthesis of RNA oligonucleotides up to 60 bases in length regardless of sequence or secondary structure.

5:30 End of Conference

Call for Posters

Call for Posters
Industry and academic scientists are encouraged to submit poster titles for this event. One-page abstracts (8 1/2” x 11” with 1-inch margins) must be submitted no later than October 10th, 2001 for inclusion in conference documentation. Additional poster submissions will be accepted until November 5, 2001 but may not be included in conference documentation.
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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