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Directed evolution of tissue inhibitor of metalloproteinase 3 (TIMP-3) to develop novel Alzheimer’s disease (AD) therapeutics

Award Number: R03AG070511
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2022
PERIOD OF PERFORMANCE END DATE: 06/30/2025

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Directed evolution of tissue inhibitor of metalloproteinase 3 (TIMP-3) to develop novel Alzheimer’s disease (AD) therapeutics - SUMMARY Limited efficient therapeutics are available to control Alzheimer's disease (AD), so there is a strong demand to target new pathogenic biomarkers of AD. The metzincin superfamily, including matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinases (ADAMs), play a multifaceted role in physiological and pathological processes in the central nervous system and therefore are therapeutic targets to limit neurodegeneration in AD. For instance, upregulation of MMP-9 promotes apoptosis, blood-brain barrier disorder, and demyelination and is involved in the amyloid-β processing pathway through proteolytic degradation of extracellular matrix components and tissue remodeling, and increasing tau accumulation which play key roles in AD. But on the other hand, upregulation of ADAM-10 increases soluble amyloid-β formation, which helps control AD. Thus, using highly selective inhibitors to tailor the proteolytic activity of metzincin- induced pathological changes in AD patients’ brains may be a promising therapeutic strategy. Protein inhibitors offer higher selectivity to target MMP-9 compared to smaller synthetic inhibitory molecules with broad-spectrum targets. Tissue inhibitors of metalloproteinases (TIMPs) are the major endogenous inhibitors of MMPs and ADAMs with varying degrees of binding affinity. Among all TIMPs, TIMP-3 has the lowest association with the cell signaling molecules triggering undesired off-target effect such as the ones responsible in tumorigenesis, suggesting that it has a low off-target therapeutic effect in MMP-dependent diseases. This makes TIMP-3 an ideal protein scaffold for engineering improved inhibitors for MMP-9. However, TIMP-3 also binds to other MMPs, ADAMs, and growth factors. Here, we propose to use a combination of rational and random combinatorial approaches to develop TIMP-3-based therapeutics to control neurodegenerative disease progression by targeting MMP-9 with high selectivity. These engineered TIMP-based probes will avoid binding to ADAM-10, which is neuroprotective in AD, to decrease off-target effects. The overarching goal of this project is to engineer and design a new molecularly targeted therapy based on natural MMP inhibitors that target MMP-9 with high selectivity, understand their mechanism of inhibition using structural studies and cell culture models to improve outcomes in neurodegenerative diseases with inadequate treatment options.


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 = -$2,762 )
2026	2022	BOARD OF REGENTS OF NEVADA SYSTEM OF HIGHER EDUCATION	1664 N VIRGINIA ST	RENO	NV	89557	WASHOE	USA	Aging Research	000	1	12/9/2025	NEW	-$2,762
														Subtotal = -$2,762

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	BOARD OF REGENTS OF THE NEVADA SYSTEM OF HIGHER ED	1664 N VIRGINIA ST # 285	RENO	NV	89557	WASHOE	USA	Aging Research	000	1	4/12/2024	NEW	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $299,975 )
2022	2022	NEVADA SYSTEM OF HIGHER EDUCATION	1664 N VIRGINIA ST	RENO	NV	89557	WASHOE	USA	Aging Research	000	1	6/2/2022	NEW	$299,975
														Subtotal = $299,975

Grand Total All Awards = $297,213

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Directed evolution of tissue inhibitor of metalloproteinase 3 (TIMP-3) to develop novel Alzheimer’s disease (AD) therapeutics

Award Number: R03AG070511

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2022

PERIOD OF PERFORMANCE END DATE: 06/30/2025

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