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Compound repositioning for Alzheimer's Disease using knowledge graphs, insurance claims data, and gene expression complementarity

Award Number: R01AG066750
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY This proposal focuses on the challenge of identifying drug repositioning candidates for Alzheimer’s Disease. The foundation of this work is the ReFRAME library, a set of ~13,000 compounds that includes nearly all small molecules that have been FDA-approved, reached clinical development, or undergone significant preclinical profiling. The ReFRAME library is being actively screened against a diverse cross-section of in vitro assays. This proposal pursues three distinct strategies for identifying repositioning candidates among the ReFRAME collection. First, we will create and mine a large and heterogeneous biomedical knowledge graph. We will use machine learning methods to identify repositioning candidates based on properties of the knowledge graph surrounding and joining each drug and disease. Second, we will mine a massive data set of insurance claims data for associations between drug use and the incidence or severity of Alzheimer’s Disease. Containing almost 7 billion medical claims and over 2 billion pharmacy claims, this data set represents the largest source of claims data available. Third, we will use concept of gene expression complementarity to identify repositioning candidates. We will generate a gene expression signature for every ReFRAME compound in three cell lines relevant to Alzheimer’s Disease, and we will screen for compounds that produce a signature that appear to reverse gene expression changes seen in Alzheimer’s Disease. After assembling repositioning candidates identified through all three of these methods, we will prioritize up to 100 compounds (or compound combinations) for further characterization and validation. These follow-up experiments will initially investigate the activity of these compounds in five cell-based assays to establish a mechanistic hypothesis on their mechanism of action in Alzheimer’s Disease. Secondary follow-up experiments may include validation in some combination of in vitro (including hiPSC-derived cerebrocortical neurons and/or organoids) and in vivo systems. We believe that the multifaceted approach described in this proposal offers the best possible chance at successfully identifying AD repositioning candidates. Moreover, this work will create methods and resources that will be useful to the broader scientific community, both for Alzheimer’s Disease and for other disease areas.


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: 2024 ( Subtotal = $789,486 )
2024	2024	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	000	5	12/7/2023	NON-COMPETING CONTINUATION	$789,486
														Subtotal = $789,486

Issue Date FY: 2023 ( Subtotal = $885,966 )
2023	2023	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	000	4	1/19/2023	NON-COMPETING CONTINUATION	$885,966
2023	2023	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	001	4	9/14/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $885,966

Issue Date FY: 2022 ( Subtotal = $886,543 )
2022	2022	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	000	3	1/24/2022	NON-COMPETING CONTINUATION	$797,889
2022	2022	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	001	3	5/3/2022	NON-COMPETING CONTINUATION	$88,654
														Subtotal = $886,543

Issue Date FY: 2021 ( Subtotal = $886,543 )
2021	2021	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	000	2	2/2/2021	NON-COMPETING CONTINUATION	$886,543
														Subtotal = $886,543

Issue Date FY: 2020 ( Subtotal = $885,874 )
2020	2020	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	001	1	6/3/2020	NEW	-$79,854
2020	2020	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	000	1	4/2/2020	NEW	$965,728
														Subtotal = $885,874

Grand Total All Awards = $4,334,412

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Compound repositioning for Alzheimer's Disease using knowledge graphs, insurance claims data, and gene expression complementarity

Award Number: R01AG066750

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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