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The Conundrum of Absentee Receptors: Efficacy Potentiation Through Drug-Receptor Modulation

Award Number: R01AR081264
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: 09/21/2022
PERIOD OF PERFORMANCE END DATE: 06/30/2027

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The Conundrum of Absentee Receptors: Efficacy Potentiation Through Drug-Receptor Modulation - PROJECT SUMMARY/ABSTRACT This proposal outlines an advanced drug delivery methodology, argues for the power of biotherapeutics, and demonstrates increased biotherapeutic efficacy through receptor upregulation. The benefit of specificity that is inherent to targeted biotherapeutics comes at the cost of predicated efficacy based on the cognate receptor being present at a high enough density to achieve a therapeutic effect. Current advances in delivery systems are enabling localized and prolonged drug release. However, localization is only one component of effective drug administration. Here, we propose an advanced drug delivery system, rationally designed to potentiate drug activity while simultaneously localizing and prolonging biotherapeutic concentration. As a clinically relevant example, this proposal outlines the coordinated localization and potentiation of the natural antifibrotic peptide hormone, relaxin-2 (RLX), and its receptor, RXFP1, to both treat the underlying causes of shoulder contracture and to restore joint range of motion. RLX remodels extracellular matrix (ECM) proteins via upregulating matrix metalloproteases (MMPs) and decreasing collagen levels. We recently made the exciting discovery that dexamethasone (DEX) increases RXFP1 expression in fibrotic synoviocytes and further exploration of the molecular mechanism of actions of RLX and DEX will enhance rational drug design. We will test the hypothesis that co-administration of RLX and DEX from polymeric microparticles (MPs) via a local single intraarticular (IA) injection into the synovial space, will rapidly alleviate arthrofibrosis symptoms (increased joint stiffness and decreased range of motion, ROM) and reduce fibrotic tissue accumulation in the afflicted joint. Further, DEX potentiation of RLX’s antifibrotic activity will decrease the minimum effective dose and increase recovery rate by modulating RXFP1 receptor density. Successful completion of this proposal will provide a novel treatment for arthrofibrosis, a debilitating condition which affects more than 15 million people in the United States, and demonstrate the importance of both delivering a biotherapeutic while also increasing the target receptor density to maximize efficacy. Importantly, significant 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 these hypotheses. The specific aims of this five-year proposal are as follows. Aim 1 determines RLX’s ligand-receptor binding mechanics and the novel role of TGF-β1 and DEX in regulating RXFP1 expression, as well as RLX’s antifibrotic mechanism of action. Aim 2 identifies the material property characteristics of biodegradable and biocompatible polymeric MPs loaded with either DEX or RLX. Aim 3 evaluates the pharmacokinetics and efficacy of the optimal DEX MP + RLX MP codelivery formulation cocktail 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 = $629,586 )
2025	2025	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	6/23/2025	NON-COMPETING CONTINUATION	$629,586
														Subtotal = $629,586

Issue Date FY: 2024 ( Subtotal = $628,970 )
2024	2024	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	6/24/2024	NON-COMPETING CONTINUATION	$628,970
														Subtotal = $628,970

Issue Date FY: 2023 ( Subtotal = $652,797 )
2023	2023	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	2	7/26/2023	NON-COMPETING CONTINUATION	$652,797
2023	2022	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	2/2/2023	NEW	$0
														Subtotal = $652,797

Issue Date FY: 2022 ( Subtotal = $649,942 )
2022	2022	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	9/21/2022	NEW	$649,942
														Subtotal = $649,942

Grand Total All Awards = $2,561,295

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The Conundrum of Absentee Receptors: Efficacy Potentiation Through Drug-Receptor Modulation

Award Number: R01AR081264

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: 09/21/2022

PERIOD OF PERFORMANCE END DATE: 06/30/2027

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