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TREM2 Genotype-Informed Drug Repurposing and Combination Therapy Design for Alzheimers Disease

Award Number: R01AG076448
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/15/2022
PERIOD OF PERFORMANCE END DATE: 03/31/2027

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TREM2 Genotype-Informed Drug Repurposing and Combination Therapy Design for Alzheimers Disease - PROJECT SUMMARY The cumulative evidence indicates neuro-inflammation play crucial roles in Alzheimer’s disease (AD) and anti- inflammatory agents (i.e., microglia-targeted therapies) show potential treatments for AD. The treatment window for microglia-targeted therapies may at least be open later in AD due to the nature of microglial biology. If amyloid-β is the trigger for AD, and tau is the executioner, then microglia are accelerators of disease progression. Microglia-targeted approaches have a better chance of success in mild to moderate disease compared to anti-amyloid therapies that have to prevent the trigger early in AD. Among the microglial genes, triggering receptor expressed on myeloid cells 2 (TREM2) has received much attention because a hemizygous R47H variant of TREM2 (TREM2R47H) increases the AD risk by 2-7 folds in various populations, including African American. Our preliminary single-nucleus RNA-sequencing (snRNAseq) study identified disease-associated microglia (DAM) with enhanced AD pro-inflammatory signatures (i.e., activation of Akt-signaling) associated with the TREM2R47H variant and pharmacological Akt inhibition reversed the TREM2R47H induced inflammation, showing proof-of-concept of TREM2R47H targeted drug discovery in AD. Using multimodal snRNAseq analysis, we identified two approved anti-inflammatory asthma drugs (fluticasone and mometasone) that were predicted to modulate DAM molecular networks are associated with a reduced incidence of AD in electronic health record (EHR) data of 7 million patients. We therefore posit that understanding how the AD-linked mutations (i.e., TREM2R47H) enhance microglial toxicity could lead to understanding how microglia become maladaptive/toxic and development of microglia-targeted therapeutic strategy for late-onset sporadic AD in general. This application calls for novel microglia-targeted drug repurposing and combination therapies for AD using our well-established multi-omics and deep learning-based EHR approaches, and functional observations in AD patient-induced pluripotent stem cells (iPSCs), cerebral organoids, and mouse models, with three specific Aims. Aim 1 will test the TREM2R47H informed microglia-targeted therapeutic hypothesis for identifying cell type-specific molecular drivers/networks, repurposable drugs, and combination therapies for AD using multi-omics evidence aggregation. These analyses will leverage our existing snRNAseq data (n = 24 TREM2R47H and n = 23 common variant (CV)-TREM2 with matched age, AD pathology and APOE genotypes) and public genomic data from the AD knowledge portal. Aim 2 will identify repurposable drugs and combination therapies using high-throughput EHR-based hypothesis generation and sequential deep learning-based propensity score matching approaches. We will leverage de-identified EHRs from the INSIGHT networks (~11 million patients across New York City’s 5 health systems and the greater metropolitan area). Aim 3 will screen, test and validate drugs using AD patient- derived iPSC lines carrying TREM2R47H in conjunction with cerebral organoid and mouse models. The successful completion of this project will offer a viable strategy to move AD drug repurposing from bench to bedside rapidly. 1


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: 2026 ( Subtotal = $794,088 )
2026	2026	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Aging Research	000	5	4/7/2026	NON-COMPETING CONTINUATION	$794,088
														Subtotal = $794,088

Issue Date FY: 2025 ( Subtotal = $781,379 )
2025	2025	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Aging Research	001	4	6/10/2025	NON-COMPETING CONTINUATION	$63,786
2025	2025	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Aging Research	000	4	3/17/2025	NON-COMPETING CONTINUATION	$717,593
														Subtotal = $781,379

Issue Date FY: 2024 ( Subtotal = $809,747 )
2024	2024	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Aging Research	000	3	4/15/2024	NON-COMPETING CONTINUATION	$809,747
														Subtotal = $809,747

Issue Date FY: 2023 ( Subtotal = $817,408 )
2023	2023	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Aging Research	000	2	3/23/2023	NON-COMPETING CONTINUATION	$817,408
														Subtotal = $817,408

Issue Date FY: 2022 ( Subtotal = $831,528 )
2022	2022	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Aging Research	000	1	7/14/2022	NEW	$831,528
														Subtotal = $831,528

Grand Total All Awards = $4,034,150

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TREM2 Genotype-Informed Drug Repurposing and Combination Therapy Design for Alzheimers Disease

Award Number: R01AG076448

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/15/2022

PERIOD OF PERFORMANCE END DATE: 03/31/2027

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Department of Health & Human Services

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Award Information

TREM2 Genotype-Informed Drug Repurposing and Combination Therapy Design for Alzheimers Disease

Award Number: R01AG076448

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/15/2022

PERIOD OF PERFORMANCE END DATE: 03/31/2027

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer

TREM2 Genotype-Informed Drug Repurposing and Combination Therapy Design for Alzheimers Disease