Arthrofibrosis control using small molecule inhibitors of interleukin-11

ABSTRACT This program aims to develop and commercialize a novel, safe, and effective therapy for arthrofibrosis (AF) to reduce and potentially reverse fibrous tissue deposition, reduce pain and stiffness, and improve the range of motion in affected joints. AF is characterized by the excessive buildup of fibrous collagen within joint structures such as the synovium. It often occurs in end-stage osteoarthritis (OA) around joint replacement surgery, prolonged immobilization following skeletal injury, and after anterior cruciate ligament repair. Current treatment methods, such as manipulation under anesthesia and invasive arthrolysis, are not always completely effective in relieving the pain and limited movement associated with AF. To address this issue, we propose to investigate a new therapeutic approach for AF that involves local application of NovoMedix small-molecule anti-inflammatory and antifibrotic drug candidates (NMX), which have been recently found to reverse differentiation of myofibroblasts and prevent their abnormal deposition of collagen during idiopathic pulmonary fibrosis (IPF). Based on successful studies in IPF models, we anticipate that NMX can minimize AF in fibroblastic synovial cells derived from OA patients and in a rat model of AF following acute joint injury with prolonged immobilization. The Marrero laboratory is poised to execute the proposed approach because of its orthopedic resources and extensive participation in select projects involving disease and surgical rodent models of arthritis, limb amputation, and studies requiring rodent arthrotomy and joint repair. The specific aims for this project are: 1) assess the effectiveness of 10 different NMX analogs in reducing fibrotic characteristics in fibrotic synovial cells, confirm efficacy in cultured osteoarthritis patient-derived synovial cells, and select 3 drug candidates for testing in animals, and 2) test the effectiveness of intra-articular NMX on improvement in joint movement and reduced fibrous tissue in a rat model of post-traumatic immobilization-induced AF. This will allow us to select a drug candidate to move into IND-enabling studies to conduct a Phase 1 clinical trial.