Targeted delivery of relaxin-2 as a novel protein therapeutic for the treatment of fibrotic diseases
Embargo Date
2027-02-12
OA Version
Citation
Abstract
Fibrotic diseases affect thousands of individuals across various organs, yet there is no standard of care or curative option available when it comes to treatment. Fibrosis displays significant heterogeneity in its cause, onset timeline and severity across patients and tissues. Despite these differences, the foundation of fibrosis development remains consistent. It is caused by a dysregulated wound healing response to inflammation due to tissue injury. This inflammatory stimulus can result from infection, toxins, physical damage, autoimmunity or arise idiopathically. The normal healing processes become overactive, resulting in deposition of stiff extracellular matrix (ECM) proteins that causes the tissue to become impaired and lose functionality. In all forms of fibrosis, patient quality of life is impacted, whether from uncomfortable and unattractive scars on the skin, or loss of internal organ function resulting in death. Through various complex and interconnected positive feedback mechanisms, fibrotic signaling cascades and ECM build-up are constantly stimulated, making prevention and early treatment critical to success. In this work, we address some of the challenges of treating fibrotic diseases using the endogenous peptide hormone, human relaxin-2 (RLX-2), combined with mechanisms to enhance its therapeutic potential and antifibrotic efficacy. RLX-2 is a natural antifibrotic and antifibrogenic with the ability to both inhibit pathways responsible for fibrosis development and upregulate enzymes to degrade the stiffened matrix, making it poised as both a prophylactic and a treatment for established disease. However, RLX-2 has failed in previous clinical trials due to lack of efficacy. We hypothesize that these failures were due to inadequate concentration at the target tissue due to systemic delivery, as well as fibrosis-specific alterations to the RLX-2 receptor, RXFP1. We explore the antifibrotic effects of RLX-2 and methods to improve its efficacy in three different fibrotic diseases. First, we encapsulate RLX-2 into a polymeric microparticle formulation for the treatment of shoulder arthrofibrosis. Second, we are developing a sustained-release hydrogel for RLX-2 application to deep dermal wounds for the prevention and potential reversal of hypertrophic and keloid scars. Last, we explore RXFP1 gene expression in scleroderma patient dermal fibroblasts and demonstrate use of a corticosteroid to upregulate RXFP1 and potentiate the antifibrotic effects of RLX-2. Through targeted delivery strategies and understanding the pathology of the disease and target, these studies demonstrate methods to improve RLX-2’s therapeutic potential to treat fibroses.
Description
2024