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Sustained Release Relaxin-2 for the Treatment of Frozen Shoulder

Award Number: R01AR079489
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: 08/01/2022
PERIOD OF PERFORMANCE END DATE: 05/31/2027

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Sustained Release Relaxin-2 for the Treatment of Frozen Shoulder - PROJECT SUMMARY/ABSTRACT This proposal describes an innovative and restorative treatment for shoulder arthrofibrosis, also known as frozen shoulder. Of the 15 million individuals in the United States suffering from shoulder arthrofibrosis, more than 1.6 million seek medical care each year. Current treatment options, including intraarticular corticosteroid injections, non-steroidal anti-inflammatory drugs (NSAIDs), and nerve blockers, provide only marginal and temporary relief of patient symptoms and do not address the underlying cause of the disease – the accumulation of fibrotic collagenous tissue. Physical therapy is a main treatment option but it is prolonged and suboptimal. Surgical interventions are used in severe cases, but these procedures are fraught with complications and can further aggravate the fibrosis. We propose the use of human relaxin-2 (RLX) as a novel therapeutic for the treatment of shoulder arthrofibrosis. RLX is an endogenous 6-kDa peptide hormone that primarily aids in softening of the pubic symphysis and pelvic ligaments prior to childbirth via extracellular matrix remodeling. Repurposing this antifibrotic peptide to treat arthrofibrosis represents a first-of-its-kind protein therapy for this disease. Specifically, we describe detailed mechanism-of-action studies for RLX in the joint space combined with encapsulation and sustained delivery of RLX from microparticles prepared from both novel and well-established biocompatible and biodegradable polymers. The proposed experiments will define the molecular and structural basis for RLX signaling in the joint space and will use an in vivo shoulder joint contracture immobilization model to test the hypothesis that RLX reduces arthrofibrosis by inhibiting TGF-β1 signaling via the NO-sGC-cGMP pathway, thereby decreasing joint stiffness and increasing shoulder range of motion (ROM). Further, we hypothesize that sustained release of RLX from a single intraarticular injection of RLX-loaded polymeric microparticles will alleviate both the symptoms and causes of arthrofibrosis. Importantly, preliminary data support the proposed studies, well-characterized materials and rigorous experimental designs are established, and essential cross-disciplinary collaborations and expertise are in place to address the hypotheses. The specific aims of this five-year proposal are as follows. Aim 1 defines the molecular mechanism of by which RLX binds its receptor, RXFP1, providing a framework for structure-based optimization of RLX. Aim 2 determines the material property characteristics of RLX-loaded biodegradable and biocompatible polymeric microparticles, including RLX release kinetics and particle degradation. Aim 3 assesses the pharmacokinetics and efficacy of the optimal RLX-loaded microparticle formulation identified in Aim 2 using an established in vivo shoulder contracture model.


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: 2025 ( Subtotal = $601,723 )
2025	2025	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	6/18/2025	NON-COMPETING CONTINUATION	$601,723
														Subtotal = $601,723

Issue Date FY: 2024 ( Subtotal = $603,668 )
2024	2024	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	5/20/2024	NON-COMPETING CONTINUATION	$603,668
														Subtotal = $603,668

Issue Date FY: 2023 ( Subtotal = $625,269 )
2023	2023	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	5/19/2023	NON-COMPETING CONTINUATION	$625,269
														Subtotal = $625,269

Issue Date FY: 2022 ( Subtotal = $621,398 )
2022	2022	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	7/20/2022	NEW	$621,398
														Subtotal = $621,398

Grand Total All Awards = $2,452,058

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Sustained Release Relaxin-2 for the Treatment of Frozen Shoulder

Award Number: R01AR079489

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: 08/01/2022

PERIOD OF PERFORMANCE END DATE: 05/31/2027

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