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CHEMICAL MODIFICATION TO IMPROVE SIRNA PHARMACOKINETICS IN ANIMALS

Award Number: R43GM076793
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: HEALTH SERVICES
PERIOD OF PERFORMANCE START DATE: 06/01/2006
PERIOD OF PERFORMANCE END DATE: 12/31/2006

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CHEMICAL MODIFICATION TO IMPROVE SIRNA PHARMACOKINETICS IN ANIMALS - DESCRIPTION (provided by applicant): The overall goal of this project is to exploit the RNA interference (RNAi) mechanism in order to develop therapeutics to treat human disease. Because the RNAi mechanism is extraordinarily potent at reducing expression of a specific gene, it offers an opportunity to rationally design drugs targeted to individual genes in a disease implicated pathway. While this paradigm has largely been realized in cell culture using cationic lipids to introduce substrates for the RNAi pathway into mammalian cells, the widespread application of RNAi technology to gene downregulation in animals remains elusive. This is largely due to the poor pharmacokinetic (PK) properties of RNAi based drugs such as small interfering RNAs (siRNAs). We believe that that unmodified siRNA will fail as systemically administered drugs due to the poor PK properties of RNA, in particular insufficient stability in biological fluids such as blood, and suboptimal penetration into cells and uptake by tissues. We intend overcome these limitations by "employing our knowledge of the structure-activity relationships (SAR) of siRNAs to design analogs which have the potential to exhibit improved PK properties, yet maintain the high intrinsic potency of siRNA in reducing target gene expression. We will then evaluate these improved siRNA designs in preliminary pharmacokinetic and pharmacology studies in order to assess their ability to serve as leads for the development of robust RNAi based therapeutics. The deliverable from the first phase this project is one or more chemically modified siRNA constructs which show improved pharmacokinetic properties in animals relative to unmodified siRNAs. This work will be expanded in the second phase of the project to provide optimized motifs which have superior pharmacokinetics and show robust pharmacology in animal models of human disease. Because of our focus on a novel target relevant to cancer chemotherapy, we will also generate therapeutic leads appropriate for pre-clinical drug development activities. The deliverable from the project will be optimized siRNA constructs which are widely applicable to the modulation of gene expression in animals.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2006 ( Subtotal = $99,187 )
2006	2006	ISIS PHARMACEUTICALS	2292 FARADAY AVE	CARLSBAD	CA	92008	SAN DIEGO	USA	Biomedical Research and Research Training	000	1	5/18/2006	NEW	$99,187
														Subtotal = $99,187

Grand Total All Awards = $99,187

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CHEMICAL MODIFICATION TO IMPROVE SIRNA PHARMACOKINETICS IN ANIMALS

Award Number: R43GM076793

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: HEALTH SERVICES

PERIOD OF PERFORMANCE START DATE: 06/01/2006

PERIOD OF PERFORMANCE END DATE: 12/31/2006

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