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Development of Small Molecules that Enhance the Delivery and the Pharmacological Effects of Oligonucleotides

Award Number: R41TR001330
ORGANIZATION: NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/15/2015
PERIOD OF PERFORMANCE END DATE: 08/14/2017

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Development of Small Molecules that Enhance the Delivery and the Pharmacological Effects of Oligonucleotides - ¿ DESCRIPTION (provided by applicant): Antisense and siRNA oligonucleotides offer the promise of highly precise manipulation of genes involved in disease pathogenesis. However, despite the investment of enormous resources, that promise has been fulfilled to only a limited degree. A key impediment to oligonucleotide-based therapeutics is the difficulty in delivering these large, highly polar molecules to their sites of action in the cytosol or nucleus of tissue cells. While chemical modification of oligonucleotides and the utilization of various nanotechnology-based delivery approaches have been helpful, the delivery problem remains challenging. Much of the oligonucleotide accumulated by cells remains non-productively entrapped in endosomes. The complex pathways of endocytosis and intracellular trafficking are being increasingly understood at the molecular level; however, there is a paucity of small molecule probes for these pathways. Here we describe a novel technology based on the use of small organic molecules to enhance the functional delivery and pharmacological effectiveness of oligonucleotides by manipulating their intracellular trafficking. We have established a proof of principle for this strategy by identifying compounds using a high throughout screen of >100,000 small molecules. Three distinct compound series were discovered from this screen that significantly enhance oligonucleotide effects in cell culture, and in one case in a transgenic mouse model. We now propose medicinal chemistry efforts to build structure activity relationships and improve both potency and pharmacological properties with the end goal of creating molecules that can effectively and safely be used in vivo. Promising leads will be examined for their pharmacokinetic and biodistribution behavior. Finally, these leads will be evaluated in a xenograft tumor model. The identification of potent and non-toxic enhancing molecules will likely have a major impact on the entire field of oligonucleotide therapeutics.


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: 2018 ( Subtotal = $0 )
2018	2015	INITOS PHARMACEUTICALS LLC	408 LYONS RD	CHAPEL HILL	NC	27514	ORANGE	USA	National Center for Advancing Translational Sciences	000	1	1/17/2018	NEW	$0
														Subtotal = $0

Issue Date FY: 2015 ( Subtotal = $312,031 )
2015	2015	INITOS PHARMACEUTICALS LLC	408 LYONS RD	CHAPEL HILL	NC	27514	ORANGE	USA	National Center for Advancing Translational Sciences	000	1	8/13/2015	NEW	$312,031
														Subtotal = $312,031

Grand Total All Awards = $312,031

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Development of Small Molecules that Enhance the Delivery and the Pharmacological Effects of Oligonucleotides

Award Number: R41TR001330

ORGANIZATION: NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/15/2015

PERIOD OF PERFORMANCE END DATE: 08/14/2017

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