Intraarticular injection of Wnt inhibitor for osteoarthritis therapy

Osteoarthritis (OA), the most common form of arthritis, is a degenerative joint disease characterized by dysfunction of articular chondrocytes, articular cartilage degradation, osteophyte formation, and subchondral sclerosis. OA affects nearly 21 million people in the United States. It is estimated that 80% of the population will have radiographic evidence of OA by age 65. The progression of OA is slow and eventually results in destruction and total loss of articular cartilage of various joints, including fingers, knees, hips, shoulders and spine. The disease process leads to limitation of joint movement, joint deformity, joint stiffness, inflammation, and severe pain. Whereas there are several strategies to reduce symptoms, there are few therapeutic approaches for OA. Treatments for OA include nonsteroidal anti- inflammatory drugs and local injections of glucocorticoid or hyaluronic acid, and joint replacement surgery. The lifetime of the implants may become too limited for the increased life expectancy of patients, thus leading to revision surgery, which is often challenging in the elderly. Currently, there are no disease-modifying OA drugs (DMOADs) available to the huge groups of patients to delay the OA progression and regenerate damaged cartilage. Clinically, an effective DMOAD may intervene early-stage OA and obviate the need for symptom management medications, and possibly, joint replacement. The homeostasis of the articular cartilage is tightly regulated by molecular cascades controlling chondrocytes proliferation, differentiation, apoptosis, and senescence. We investigated the role of Wnt signaling in the progression of OA. We identified that elevated Wnt signaling is the direct cause of OA, while sclerostin, a Wnt signal inhibitor, is a potent disease modifying agent. To develop a clinical feasible, minimally invasive, injectable DMOAD, we have engineered StemJelTM by encapsulating sclerostin into high molecular weight hyaluronic acid (HMW-HA) to achieve a sustained-release kinetics. The overarching goal of the SBIR project is to develop a minimally invasive and injectable, disease-modifying therapy for synovial joint OA. We will optimize the formulation using rat knee OA model and assess the local and systemic toxicity. The data will prove the feasibility, technical merit, and commercial potential of StemJelTM for knee and other synovial joint OA therapy.