You are here

New Reagents for Synthesis of High Potency siRNA

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 2R44GM084552-03
Agency Tracking Number: GM084552
Amount: $949,235.00
Phase: Phase II
Program: SBIR
Solicitation Topic Code: NIGMS
Solicitation Number: PHS2010-2
Timeline
Solicitation Year: 2010
Award Year: 2010
Award Start Date (Proposal Award Date): N/A
Award End Date (Contract End Date): N/A
Small Business Information
AM BIOTECHNOLOGIES, LLC 12521 Gulf Freeway
Houston, TX -
United States
DUNS: 788679244
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 XIANBIN YANG
 (409) 747-6800
 XIYANG@UTMB.EDU
Business Contact
Phone: (281) 794-2333
Email: mark.shumbera@thioaptamer.com
Research Institution
N/A
Abstract

DESCRIPTION (provided by applicant): New Reagents for Synthesis of High Potency siRNAs Abstract Since the discovery of short interfering RNA (siRNA) molecules in the late 1990s, siRNA technology has developed rapidly as a powerful tool for functional genomic analysis, target validation and therapeutic purposes. However, the potency and persistence of unmodified siRNAs is dramatically limited by their sensitivity to nuclease degradation. Developing chemically modified siRNA duplexes with higher potency and improved nuclease resistance is essential, especially for therapeutics applications in vivo. In Phase I of this project, we demonstrated proof of principle for a new approach using phosphorodithioate siRNAs (PS2- siRNAs), prepared using novel ribonucleoside thiophosphoramidite reagents (R-thioamidites). We successfully synthesized the four ribonucleoside thiophosphoramidites (A, C, G, and U) at small scale and used them to synthesize a variety of PS2-siRNAs. Importantly, we showed that PS2-siRNAs had increased gene silencing activity against multiple different gene targets in cultured cells. These results demonstrate that PS2-siRNAs have the potential to greatly improve siRNA-based research and drug development. To achieve that potential, Phase II of this project will achieve the following aims: (1) increase the scale of R-thioamidite production; (2) optimize protocols for solid-phase synthesis of PS2-siRNA for in vitro and in vivo applications; (3) synthesize and screen several PS2-siRNA libraries to identify design rules that maximize the gene silencing activity of PS2-siRNAs; (4) demonstrate increased potency and antitumor efficacy of unformulated PS2-siRNAs in a murine model of metastatic colorectal cancer; (5) develop formulated PS2-siRNAs that provide increased potency and antitumor efficacy in a murine model of metastatic ovarian cancer. Successful completion of this project will demonstrate the value of PS2-siRNAs in vivo, and enable AM and its commercial partners to proceed with full commercialization of the R-thioamidite reagents and contribute toward the realization of effective siRNA-based therapeutics. PUBLIC HEALTH RELEVANCE: New Reagents for Synthesis of High Potency siRNAs Narrative The possible therapeutic applications of small interfering RNA (siRNA) are broad and far reaching for many diseases. However, chemically unmodified siRNA molecules are rapidly degraded by nucleases, and often have inadequate potency, especially in animals. The need to develop nuclease resistant siRNAs with improved activity in vivo is critical to the development of novel siRNA-based therapies, as well as for many research applications of siRNA. AM is developing a novel type of chemically-modified siRNA that is expected to significantly improve siRNA potency and stability, which may lead to improved treatments for multiple human diseases.

* Information listed above is at the time of submission. *

US Flag An Official Website of the United States Government