Bone-targeted delivery of TGFβ inhibition for osteoarthritis

Othro Therapeutics, Inc., Baltimore MD

Investigators

Abstract

Abstract Osteoarthritis (OA) is the most common degenerative joint disorders and the leading cause of physical disability. There is no effective disease modifying treatment for OA except the joint replacement surgery. We have revealed that aberrant subchondral bone remodeling leads to degeneration of joint articular cartilage. Elevated osteoclast resorption in the OA subchondral bone leads to excessive TGF?1 that uncouples bone resorption and formation and resulted in deterioration of subchondral bone. Restoring the structural integrity of subchondral bone by inhibiting TGF? activity in subchondral bone can prevent OA progression and cartilage degeneration. Pain is the most prominent symptom of OA that urged people to seek for medical care. Our preliminary study suggests that osteoclasts derived factor induces axonal extrusion and innervations in the subchondral bone and substantially contribute OA pain. Zoledronic acid, a bisphosphonate that inhibits osteoclasts activity, has been reported effective in reducing knee pain and the BMLs size. Suppressing of TGF? signaling pathway with type I TGF? receptor inhibitor has been demonstrated to rescue subchondral bone pathology and attenuate cartilage degeneration. However, TGF?s are multifunctional cytokines that are involved in a range of biological processes. Systemic inhibition of TGF? signaling may lead to a failure in the maintenance of tissue homeostasis of other organs, particularly articular cartilage where TGF? severs as a major anabolic factor. Thus, it is of great importance to develop a novel strategy that can retain or perhaps even increase the efficacy of the TGF? inhibitor while improving its safety in the therapeutic applications. We have synthesized a novel drug that conjugates alendronate (ALN), a bisphosphonate drug, with LY 2109761 (LY), a selective T?RI and T?RII kinase inhibitor, through a metabolically cleavable linker. Utilizing the high affinity of ALN, we achieve bone targeted delivery and sustained bone release of T?R inhibitor. Moreover, we anticipate that this conjugate has superior effect in alleviating OA pain as ALN has also been known to relieve bone pain. In this application, we propose to investigate the effects of the conjugate in preventing the development of osteoarthritic pathologies as well as alleviating joint pain. We will also optimize the treatment dosage, frequency and evaluate the toxicity of the conjugate in OA animal model. The results are expected to provide a strong technological and theoretical foundation for future clinical trials.