This proposal targets the Fiscal Year 2017 Peer Reviewed Medical Research Program Focus Area of Post-Traumatic Osteoarthritis (PTOA) and specifically addresses the following two areas of encouragement:

• “Sustained release, intra-articular injectable steroidal, non-steroidal, or disease-modifying therapies that offer two or more months of symptomatic relief of pain and/or inflammation in a single injection.”

• “Therapies that target multiple phases of the cellular response pathways implicated in the development of PTOA, including cell death, inflammation, matrix changes, and changes in catabolic/anabolic responses.”

Almost all common joint injuries, especially among military personnel, will become arthritic over 2-10 years. Arthritis poses a major health problem due to severe pain that limits mobility, which leads to obesity, cardiovascular diseases, diabetes, depression, and eventually an overall decline in health. Based on our latest findings of the underlying causes of PTOA at the molecular and cellular levels, we believe that we can develop a simple and side-effect-free intervention to prevent this type of arthritis, by delivering a single shot of our proposed medicine into the injured joint.

Current clinical treatments of common joint injuries only focus on treating symptoms such as pain and therefore do little to stop or slow down the harmful effects of the ensuing inflammatory injury response, which further damages joint tissues and causes PTOA. Our body reacts to injury by mounting an immediate and very strong acute injury response at the molecular and cellular levels, which occurs within the first hours to days after an injury, and directly contributes to PTOA development within 2-10 years. Therefore, our team’s novel therapeutic strategy is to stop the initial injury response before it can damage the joint tissue.

Our proposed PTOA preventive medicine contains two components. The active drug component is a U.S. Food and Drug Administration (FDA)-approved “orphan drug” that is a small-molecule proven by us to inhibit acute injury responses and prevent PTOA in animal models. The second component consists of a drug delivery vehicle that slowly releases the active component over several weeks to provide continued protection. This delivery vehicle has also just received FDA approval as a carrier for another steroid drug that relieves pain/inflammation in arthritic patients. Using our proposed medicine, we have successfully prevented PTOA after joint injury in mouse and rat models. Our drug formulation shows multiple benefits at the cellular level, including less cell death, inflammation, and joint tissue damage. In this proposal, we plan to test our PTOA prevention strategy in a preclinical large-animal model (sheep) to bring our drug formulation a giant step closer to human clinical trials. The primary outcome to be measured is preventing or significantly reducing PTOA after joint injury in sheep over the long term (18 months). Secondary outcomes include reduction of short-term symptoms associated with joint injury, such as inflammation, pain, and early osteoarthritis markers. Much research and development effort is also envisioned for tuning the drug formulation and delivery vehicles to achieve those outcomes.

The short-term impacts of this work include: (a) to achieve a sustained-release drug formulation of an existing FDA-approved drug that offers long-term symptomatic relief of pain and inflammation after joint injury in a single injection; (b) to prevent PTOA after joint injury in a preclinical large animal model; and (c) to attain critical information needed to fine tune formulation of the proposed therapeutics in preparation for future human clinical trials. The long-term impact is to revolutionize the current clinical practice of the “wait-and-see” approach in managing common joint injuries, which we argue should be treated promptly, in order to prevent secondary joint tissue damage and the development of PTOA. This new therapeutic strategy shall improve the quality of life for our military personnel, as well as the large numbers of civilians who suffer joint injuries.