Biotherapeutic potentiation for the treatment of musculoskeletal disease
Embargo Date
2025-05-24
OA Version
Citation
Abstract
The development of modern biotherapeutics for the treatment of musculoskeletal diseases lags behind most other disease classes. This is, in part, a result of tissue complexity, which poses significant barriers to drug delivery. However, it is also the result of under-investment in quality-of-life treatments more broadly. Unfortunately, the complexity of musculoskeletal diseases does not change reality for the tens of millions of patients each year who undergo invasive surgeries to try and relieve chronic pain. Here, we propose three unique strategies for potentiating biotherapeutics, and demonstrate their potency in treating multiple musculoskeletal diseases. The first disease we focus on is arthrofibrosis, a condition impacting 1 in 25 US adults, which limits joint range of motion and causes long term pain. An endogenously occurring peptide hormone, human relaxin-2 (RLX), shows promise as an anti-fibrotic, but multiple clinical programs have failed due to pharmacokinetic barriers and issues of receptor dysregulation. To address the pharmacokinetic limitations of RLX, we develop a tailored drug delivery system capable of sustained, intraarticular release of the anti-fibrotic. In vitro characterization demonstrates multi-week release without altering peptide structure or bioactivity. In vivo administration of RLX-loaded microparticles results in prolonged synovial concentrations of RLX and significantly decreases bioavailability in organs previously associated with RLX-induced toxicity. Finally, in a murine model of arthrofibrosis, RLX microparticles restore joint range of motion and healthy joint morphology. The other translational barrier that RLX faces is disease-state dependent downregulation of its receptor, RXFP1. We characterize fibrosis-induced changes to transcriptional and epigenetic state in synovial tissue, which contributes to receptor suppression, and identify an FDA-approved corticosteroid as a potent enhancer of RXFP1 expression. These steps pave the way for corticosteroid co-therapy to potentiate RLX's anti-fibrotic effects. For our third therapeutic platform, we develop a disease-state independent biotherapeutic circuit capable of potentiating endogenous ligands as treatments for multiple musculoskeletal diseases. Using this platform, we design therapies for arthrofibrosis, osteoarthritis, and rheumatoid arthritis. For each condition, we characterize disease state-dependent dysregulation, rationally design a biotherapeutic circuit to address this dysfunction, and demonstrate potent in vitro efficacy. The broader goal of this work is to highlight the need for cutting-edge therapies targeted at musculoskeletal diseases and that, using rationally designed biotherapeutics, even the most biomechanically complex diseases can be treated.