Validating the efficacy of SITREX in preventing heterotopic ossification

点击翻译按钮获取中文摘要

After trauma such as a blast wave-induced amputation, there is a cascade of events including inflammation, angiogenesis, fibroproliferation, and chondrogenesis that collectively contribute to osteogenesis and formation of ectopic bone at the injury site. This ectopic bone, known as heterotopic ossification, can be extremely painful and debilitating - surgical resection is the only way to treat the disease. There are no effective therapeutic treatments to prevent heterotopic ossification and we believe that is in part due to the therapeutics targeting one aspect of this trauma-response cascade, after the cascade has started. When this project started we set out to develop a Trauma-Response indEX (T-REX), that would comprise of genes that changed, facilitating the development of heterotopic ossification. We hypothesised that targeting these genes, changes to which occur at the apex of this cascade, would enable identification of a therapeutic which prevented heterotopic ossification. We used a range of next generation sequencing, molecular and cell biology approaches to identify 6 genes that would comprise the first iteration of T-REX (see approach section). After delving into this further, we found that inhibiting one gene in particular, with a silencing RNA, resulted in a 70% reduction of bone formation in vitro, in cells exposed to both trauma and ossification stimuli. To make this applicable for clinical translation, we packaged this siRNA into nanoparticles that could be delivered via a hydrogel to the site of injury. This nanoparticle laden hydrogel is our product, SITREX, and the subject of this current proposal. In this grant, our objective is to validate the effectiveness of SITREX in preventing heterotopic ossification in a 3D organotypic model in vitro, and a trauma responsive heterotopic ossification model in vivo. This objective bridges the gap between the basic science research already conducted, and translational studies. Validating the efficacy of SITREX in these heterotopic ossification models in vitro and in vivo will increase the technology readiness level, and de-risk SITREX for future funders.