Events Calendar

Title: “Multimodal Delivery of Relaxin-2 for the Treatment of Arthrofibrosis”

Advisory Committee: John Ngo, PhD – BU BME (Chair) Mark Grinstaff, PhD – BU BME/ME/MSE/MED (Advisor) Michael Albro, PhD – BU BME/MSE/ME Andrew Kruse, PhD – HMS Biological Chemistry & Molecular Pharmacology

Abstract: Relaxin-2 (RLX) is an endogenous peptide hormone with cardioprotective, angiogenic, and antifibrotic properties. It primarily mediates the necessary increases in arterial compliance and renal blood flow during pregnancy as well as serving to soften public ligaments in preparation for childbirth. RLX has been extensively researched as a clinical therapeutic. Previous clinical trials have explored using RLX to induce labor, for the treatment of acute heart failure, and as an antifibrotic for management of systemic sclerosis. Though preclinical and early stage clinical results pointed towards RLX as an effective therapeutic with a strong safety profile, it ultimately failed to meet primary endpoints in multiple Phase III trials. I argue that RLX’s clinical failures are the direct result of non-optimal drug delivery modalities as well as neglecting to consider the relationship between the RLX receptor, RXFP1, and the disease phenotype.

I propose three embodiments of RLX as an antifibrotic therapy for arthrofibrosis, a debilitating condition involving fibrotic build-up in joints that impacts millions of Americans each year with no satisfactory treatment. Each proposed treatment is designed to overcome previous clinical failures of RLX and demonstrate its clinical potential as an antifibrotic. 1) To address the rapid pharmacokinetics of systemically delivered RLX and increase specificity, I provide preclinical characterization and development of a sustained-release RLX formulation for intraarticular injection. 2) To account for receptor downregulation in the fibrotic state, I propose an RNAi-based therapy for restoration of RXFP1 expression and potentiation of RLX’s antifibrotic activity. 3) Finally, to circumvent issues of reduced RXFP1 expression, as well as the presence of non-functional, disease specific isoforms of RXFP1, I propose a broadly applicable ligand-receptor mRNA co-therapy capable of simultaneous expression of rRXFP1 and rRLX for autoinduction of RLX’s antifibrotic pathways, independent of disease state.