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Tuesday June, 10

12:00 pm Registration Open

2:00 Chairperson’s Remarks
Mark A. Kay M.D., Ph.D., Professor, Departments of Pediatrics and Genetics, Stanford University 

2:05 Systemic RNAi Therapeutics for Treating Infection
Mark A. Kay M.D., Ph.D., Professor, Departments of Pediatrics and Genetics, Stanford University 
Gene transfer vectors expressing shRNAs to target specific tissues have been utilized for treating different diseases. Interestingly, over expression of shRNAs can be toxic and even lethal because it interferes with normal microRNA processing. The rate-limiting steps in mammalian tissues as well as effective strategies to maintain a high therapeutic index will be discussed.

2:35 Delivering RNAi Therapeutics
Muthiah Manoharan Ph.D., Vice President, Drug Discovery, Alnylam Pharmaceuticals, Inc.

3:05 Delivery of Therapeutic RNA Interference into the GI tract
Johannes Fruehauf MD, Ph.D., Vice President, Research, Cequent Pharmaceuticals Inc.
Cequent has developed a system that allows the delivery of therapeutic RNA interference into the gastrointestinal tract through oral application. This method, called Transkingdom RNA interference, (tkRNAi), uses nonpathogenic bacteria that are modified to act as manufacturers and carrier vehicles of interfering RNA against genes of interest. Activity has so far been shown across a wide range of targets. APCmin mice are a genetic model of human colon cancer based on dysregulation of beta-catenin (CTNNB1) and the wnt pathway. They develop multiple polyps in their gastrointestinal tract resulting in decreased life span due to chronic obstruction and bleeding. Blockage of CTNNB1 in the gastrointestinal epithelium, e.g. through therapeutic RNA interference, should result in therapeutic or preventive effects. Here we show, that chronic oral treatment of APCmin mice (n=38) with tkRNAi bacteria resulted in a significant decrease of polyp formation through blockage of the CTNNB1 pathway in the gut. Tumor sizes and numbers were reduced and animals displayed fewer polyps with high grade dysplasia after oral treatment with tkRNAi bacteria conferring silencing against CTNNB1. These findings open the possibility of developing RNAi-based drugs for organs and tissues outside of the areas targeted by currently ongoing clinical trials, including the gastrointestinal tract, genitourinary tract, and the skin.

3:50 Networking Refreshment Break, Poster and Exhibit Viewing

4:30 Construction of phi29 DNA-Packaging Motor for Applications in Nanotechnology, Therapy, Diagnosis, and Drug Delivery
Peixuan Guo, Ph.D., Chair in Biomedical Engineering and Director of NIH Nanomedicine Development Center, University of Cincinnati
Bacterial virus phi29 packaging RNA (pRNA) is an ATP-binding component of the DNA packaging motor. pRNA contains aintermolecular interaction domain and a 5’/3’ helical domain. Its unique feature to form dimer, trimer, hexamer and patterned superstructures via the interaction of two interlocking loops makes it a promising tool in nanomedicine. Replacement or insertion of the 5’/3’helical domain with siRNA, ribozyme and receptor-binding aptamer or other therapeutic molecules does not interferer with the formation of the multimers, making it a novel vehicle for targeted therapy, pathogen detection and drug delivery. The chimeric siRNA/pRNA complex induced apoptosis in specific cancer cells, as tested in both cell culture and in animal trials. Such protein-free nanoparticles as therapeutic reagents would allow repeated treatment for chronic diseases.

5:00 In vivo Imaging of siRNA Delivery and Silencing in Tumors
Anna Moore, Ph.D., Associate Professor, Department of Radiology and Director, Molecular Imaging Laboratory, Massachusetts General Hospital
During the past years, RNAi has become an indispensable research instrument in virtually all fields of medical and biological sciences. Its broad applicability (virtually any gene can be silenced), superior efficiency (100-1000-fold compared to antisense oligonucleotides), and exquisite specificity (single nucleotide) could potentially be used to develop a powerful novel treatment paradigm with global relevance to any disease amenable to manipulation at the level of gene expression. The fast developing field of RNA interference requires monitoring of siRNA delivery to targeted organs and evaluating the efficiency of target gene silencing. Molecular imaging techniques represent a powerful tool for real-time non-invasive monitoring of various events at a near microscopic level and have superior advantages over conventional in vitro and cell culture research techniques in biology. Therefore, molecular imaging approach fits perfectly to fulfill the need to monitor siRNA delivery and provides information in a fast, reproducible and non-invasive manner. This presentation will summarize the existing information on various imaging modalities and their application for siRNA imaging.

5:30 Close of Day