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Small Molecules Promote Tendon Regeneration by Targeting Endogenous Stem Cells

Award Number: R41AR079360
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/05/2021
PERIOD OF PERFORMANCE END DATE: 08/31/2022

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Small Molecules Promote Tendon Regeneration by Targeting Endogenous Stem Cells - Abstract Tendon and ligament injuries represent an acute healthcare burden in the United States, costing >$30 billion annually. Tendon injuries frequently result in scar-like tissue with inferior physical properties - however no regenerative therapy exists to date. Recently, we have identified and characterized perivascular (CD146+) tendon stem/progenitor cells (TSCs) that play an essential role in tendon healing via FAK and ERK1/2 signaling. In our preliminary study, we screened small molecules from a library of FAK and ERK1/2 agonists and identified Oxotremorine M (Oxo-M) and PPBP maleate (4-PPBP) that stimulated TSCs toward regenerative tendon healing. Oxo-M and 4-PPBP were originally developed for treating neuronal diseases but have never been tested in the musculoskeletal system. In vitro, a combination of Oxo-M and 4-PPBP induced significant increases in the expression of tendon-related genes involved in tendon repair. Oxo-M and 4-PPBP showed no cytotoxicity up to 10X working doses. Western blot and siRNA knockdown (KD) confirmed that FAK and ERK1/2 signaling regulate Oxo -M & 4-PPBP-induced tenogenic differentiation of TSCs. In vivo, direct topical delivery of Oxo-M and 4-PPBP onto full-transected rat patellar tendons (PT) significantly improved tendon healing, as observed histologically as densely reorganized collagen fibrils, and functionally as significantly enhanced tensile strength. This process was guided by a rapid but transient increase in the number endogenous TSCs undergoing tenogenic differentiation. In addition, Oxo-M and 4-PPBP specifically targeted CD146+ TSCs through muscarinic acetylcholine receptors (AChRs) and σ1 receptor (σ1R) pathways, with minimal effect on other types of tendon cells. These findings demonstrate a novel and promising activity of the combination of Oxo-M and 4-PPBP in tendon healing by specifically targeting endogenous TSCs. The overall objectives of this STTR grant are to develop a reliable and effective small molecule-based regenerative therapy for tendon injuries by transiently activating regenerative pathways of endogenous TSCs and repair tendon tears. The overarching goal of the STTR phase I grant is to optimize the combination of Oxo-M and 4-PPBP, the 2 compounds and determine their drugability in combination. The 2 aims of the phase I STTR are to obtain robust proof-of-concept and preliminary safety data to establish technical merit, feasibility, and commercial potential of the innovative technology.


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: 2023 ( Subtotal = $0 )
2023	2021	WNT SCIENTIFIC LLC	156 RALEIGH ST	ROCHESTER	NY	14620	MONROE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	6/9/2023	NEW	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2021	WNT SCIENTIFIC LLC	156 RALEIGH ST	ROCHESTER	NY	14620	MONROE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	11/16/2021	NEW	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $252,131 )
2021	2021	WNT SCIENTIFIC LLC	156 RALEIGH ST	ROCHESTER	NY	14620	MONROE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	9/3/2021	NEW	$252,131
														Subtotal = $252,131

Grand Total All Awards = $252,131

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Small Molecules Promote Tendon Regeneration by Targeting Endogenous Stem Cells

Award Number: R41AR079360

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/05/2021

PERIOD OF PERFORMANCE END DATE: 08/31/2022

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