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Engineered mRNA therapeutic for rotator cuff muscle repair

Award Number: R01AR085007
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: 06/01/2026
PERIOD OF PERFORMANCE END DATE: 05/31/2030

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Engineered mRNA therapeutic for rotator cuff muscle repair - ABSTRACT Rotator cuff (RC) tears are a leading cause of musculoskeletal impairment, affecting over 250,000 individuals annually in the United States. Despite surgical repair being the standard of care, failure rates remain alarmingly high, with up to 90% of cases experiencing re-tears or poor functional recovery. This failure is largely driven by irreversible muscle degeneration, including atrophy and fatty infiltration, which impair healing and compromise surgical outcomes. Current therapies primarily target the bone-tendon interface while neglecting muscle pathology, underscoring a critical need for regenerative strategies that directly address RC muscle degeneration. This proposal aims to develop a therapeutic approach leveraging lipid nanoparticles (LNPs) encapsulating WNT7a mRNA (W7a-LNP) to promote muscle regeneration and prevent degeneration following RC injury. WNT7a has been shown to increase muscle mass, enhance muscle stem cell (MuSC) expansion, and reduce fatty infiltration, but its recombinant protein form is limited by poor bioavailability and high production costs. W7a- LNP circumvents these limitations by enabling localized, sustained WNT7a production at the injury site, transforming muscle cells into `in vivo protein factories.' Our preliminary data demonstrate that W7a-LNP reduces fibro/adipogenic progenitor (FAP) adipogenesis and fatty infiltration in both in vitro and in vivo models. We will test the hypothesis that intramuscular delivery of W7a-LNP prevents and reverses RC muscle degeneration through three specific aims. Aim 1 will engineer and validate W7a-LNP as a targeted muscle regeneration platform by optimizing delivery, evaluating WNT7a expression kinetics, and assessing its effects on MuSC expansion, myofiber hypertrophy, and FAP adipogenesis in vitro and in vivo. Aim 2 will determine the efficacy of W7a-LNP in preventing RC muscle degeneration when administered at the time of injury using a clinically relevant delayed tendon repair model. Aim 3 will evaluate W7a-LNP's ability to reverse established muscle degeneration when delivered at later stages of injury, with or without mechanical loading, to assess potential synergistic effects. The impact of this research is the development of a scalable, translatable mRNA-LNP therapy that preserves and restores muscle quality in RC injuries. By addressing a critical gap in current treatment paradigms, this strategy has the potential to improve surgical outcomes, enhance functional recovery, and reduce the need for invasive salvage procedures, ultimately transforming the management of RC muscle degeneration.


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 = $2,058,020 )
2026	2026	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	5/13/2026	NEW	$2,058,020
														Subtotal = $2,058,020

Grand Total All Awards = $2,058,020

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Engineered mRNA therapeutic for rotator cuff muscle repair

Award Number: R01AR085007

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: 06/01/2026

PERIOD OF PERFORMANCE END DATE: 05/31/2030

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