Repurposing Alpha-1-antitrypsin as a treatment for post-traumatic osteoarthritis

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Osteoarthritis (OA) is the most common joint disease that causes chronic pain and disability in hundreds of millions of people globally. Our joints work because there is a special tissue layer, called cartilage, which maintains the edge of the bones smooth and avoids attrition. If cartilage is broken down by traumatic events or eroded by ageing and also micro-traumas, there is disease characterized by joint malfunctioning (lack of mobility) and excruciating pain. Here we focus on trauma-induced ligament or cartilage injuries which contributes to over 12% of the overall OA burden worldwide: a significant proportion of these patients (~40%) develop osteoarthritis even with the best available treatments. Surgical stabilisation of the joint is the treatment for trauma-induced ligament or cartilage injuries; however, research indicates that ongoing inflammation following surgical stabilization plays a crucial role in driving progression to osteoarthritis. Therefore, we propose that early intervention with factors that mitigate inflammation and promote cartilage repair after joint injury can prevent further damage and the development of post-traumatic osteoarthritis. We have identified one such factors, and it is termed alpha1-antitrypsin (AAT).With this proposal we seek funding to study the fundamental biology of AAT in experimental post-traumatic osteoarthritis; understanding how it works can open innovative therapeutic approaches for better management of osteoarthritis. This hypothesis will be tested by three experimental objectives.1. Study the molecular mechanisms of AAT using human chondrocytes, the cells that produce the cartilage. We aim to unravel how AAT stimulates cartilage growth to repair post-traumatic defects. This involves investigating AAT interaction with counterparts on the cell surface (often called receptors) and study what happens within the cell after the interaction takes place.2. Evaluate the potential of AAT for therapeutic repair of cartilage damage. We will conduct experiments using an approved AAT product called Prolastin-C to assess its efficacy in regenerating damaged cartilage and bone defects. Our research will involve laboratory tests as well as pre-clinical models of post-traumatic osteoarthritis.3. Investigate the role of endogenous AAT on cartilage regeneration. Here we will use mice genetically modified to lack the genes that produce AAT. These animals are commercially available and viable. We will apply them to our model of joint injury, to assess if and how naturally occurring AAT contributes to cartilage maintenance and repair in the context of joint injuries.At completion this project may identify AAT as a novel disease-modifying osteoarthritic drug. Since Prolastin-C (plasma AAT, produced by Grifols) is already used to treat lung disease in individuals with the rare genetic deficiency in AAT, we reason that this project can guide a rapid repurposing trial for this new therapeutic agent. In summary, we aim to uncover the mechanisms by which AAT influences chondrocytes and promotes cartilage repair with human cells and animals with osteoarthritis. At project completion, and with further funding support, our ultimate objective is to develop AAT-based drugs that can slow down the progression of osteoarthritis and provide long-term relief for individuals suffering from the condition.