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GENE SILENCING WITH U1 ADAPTOR OLIGONUCLEOTIDES

Award Number: R43GM085863
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/15/2008
PERIOD OF PERFORMANCE END DATE: 02/09/2010

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GENE SILENCING WITH U1 ADAPTOR OLIGONUCLEOTIDES - DESCRIPTION (provided by applicant): Our understanding of complex biological phenomena and disease progression has led to the realization that changes in the expression of genes underlie many of these processes. Developing reagents that can selectively alter the expression level of any desired gene has been a goal of both scientists and clinicians for years. Historically, the most common approach was based on antisense oligonucleotides (ASOs) that encompass a broad variety of mechanisms that have in common an oligonucleotide designed to base pair with its complementary target mRNA leading to either degradation or impaired function of the mRNA. Classically, ASOs were designed to interfere with translation of the target mRNA or induce its degradation via RNase H or more recently by ribozyme activity. Current excitement has focused on RNAi that uses a distinct mechanism where oligonucleotides trigger an endogenous pre-existing gene suppression pathway that is fundamental to cellular gene regulatory networks. In spite of its general success, some mRNAs are only modestly downregulated (2-fold) by RNAi and others are refractory. Further, certain off-target effects can arise leading to unexpected consequences, underscoring the need for additional methods. The rapid rise of the RNAi field has led to an increased appreciation, of direct relevance to the present proposal, that regulatory sequence elements in mRNA 3' ends (eg. 3'UTRs) control the expression of that gene. Here we present preliminary data on the development of a new gene silencing technology that uses oligonucleotides annealing to specific sequence regions within the 3'UTR to inhibit pre-mRNA processing. We plan to improve this new technology by systematically analyzing modified bases to increase inhibitory activity. We will also determine how robust the technology is by testing its effectiveness in a variety of human cell types as well as cells from other vertebrates and by silencing several endogenous human genes as a proof-of-principle. Finally, we will also determine whether enhanced inhibition is seen when this new technology is used in conjunction with other gene silencing technologies such as RNAi where enhancement is expected because these different methods utilize fundamentally distinct mechanisms. We believe this new technology will make a significant addition to our gene silencing toolkit and may even aid emerging oligonucleotide-based therapies, although that is beyond the scope of this proposal. PUBLIC HEALTH RELEVANCE: The commercialization of this new U1 Adaptor mediated gene silencing technology will be a significant addition to the scientific research community's "gene silencing toolkit". Because this method exploits a distinctly different mechanism compared to more common gene silencing approaches, it has the potential of enhancing these traditional technologies when used in combination with them via synergistic effects. This may aid in the development of emerging oligonucleotide-based gene silencing therapies by improving sensitivity and efficacy.


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: 2010 ( Subtotal = $0 )
2010	2008	INTEGRATED DNA TECHNOLOGIES INC	1710 COMMERCIAL PARK	CORALVILLE	IA	52241	JOHNSON	USA	Biomedical Research and Research Training	000	1	1/29/2010	NEW	$0
														Subtotal = $0

Issue Date FY: 2009 ( Subtotal = $99,750 )
2009	2009	INTEGRATED DNA TECHNOLOGIES INC	1710 COMMERCIAL PARK	CORALVILLE	IA	52241	JOHNSON	USA	Trans-NIH Recovery Act Research Support	001	1	8/26/2009	SUPPLEMENT FOR EXPANSION	$0
2009	2009	INTEGRATED DNA TECHNOLOGIES INC	1710 COMMERCIAL PARK	CORALVILLE	IA	52241	JOHNSON	USA	Trans-NIH Recovery Act Research Support	000	1	8/12/2009	SUPPLEMENT FOR EXPANSION	$99,750
														Subtotal = $99,750

Issue Date FY: 2008 ( Subtotal = $170,000 )
2008	2008	INTEGRATED DNA TECHNOLOGIES INC	1710 COMMERCIAL PARK	CORALVILLE	IA	52241	JOHNSON	USA	Biomedical Research and Research Training	000	1	8/11/2008	NEW	$170,000
														Subtotal = $170,000

Grand Total All Awards = $269,750

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GENE SILENCING WITH U1 ADAPTOR OLIGONUCLEOTIDES

Award Number: R43GM085863

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/15/2008

PERIOD OF PERFORMANCE END DATE: 02/09/2010

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