A novel, first-in-its-kind, aptamer-based LYTACs to address the unmet clinical need of diabetic wounds.

糖尿病足溃疡(DFUS)是糖尿病的主要并发症，发病率约为25%，5年复发率约为65%。DFU通常以住院结束，高达60%的病例截肢。DFU相关死亡率在12个月内为5%，5年后上升至42%。尽管DFU的发病率很高，对生活质量有很大影响，但目前还没有有效的治疗方法被批准，因此DFU仍然是一种高度未得到满足的临床状况。APTADEGRAD旨在利用基于适体的溶酶体靶向嵌合体(LYTAC)治疗糖尿病足部溃疡(DFU)，为一种新颖的、一流的治疗方法获得体内概念验证。这些LYTAC将针对IL-1？及其受体IL-1R1和基质金属蛋白酶-9进行降解，这些蛋白质在糖尿病伤口的愈合障碍中发挥着关键作用。我们的假设是：a)基于适配子的LYTACs MOA，可能提供可控的，剂量依赖的减少MMP9，IL-1b及其受体IL-1R1的潜力，减缓过度的DFU炎症反应，同时保持这些蛋白质的生物有益水平，促进愈合和预防感染；b)同时靶向这些相关蛋白质将在炎症级联反应中产生协同作用，提供更好的疗效。如果项目的主要目标得以实现(即在DFU的动物模型中显示疗效)，我们将首次展示基于LYTAC的潜在治疗方法，在此情况下，用于糖尿病溃疡，并可能应用于其他类型的慢性伤口或免疫病理。除了疗效数据，我们还将收集关于LYTAC的基本知识(毒性、有效性、作用机制、与其他方法的差异，如阻断或抑制)，这些差异对于未来将LYTAC的新概念在药物开发中成功转化为临床试验至关重要。

Diabetic foot ulcers (DFUs) a major complication of diabetes, occur in ~25% of patients, with a five-year recurrence rate of ~65% . DFUs often end in hospitalization, with limb amputations in up to 60% of cases . DFU related mortality is 5% within twelve months, rising to 42% after five years. Despite high prevalence and its major impact on the quality of life, no effective treatment has been approved, so DFU remain a highly unmet clinical condition. APTADEGRAD aims at obtaining in vivo proof-of-concept for a novel, first-in-class therapy using aptamer-based Lysosome Targeted Chimeras (LYTACs) to heal diabetic foot ulcers (DFUs). These LYTACs will target IL-1ß, its receptor IL-1R1, and MMP-9 for degradation, proteins known to play a key role in impaired healing in diabetic wounds. Out hypothesis is that a) aptamer-based LYTACs MoA, may offer the potential to deliver a controlled, dose-dependent reduction of MMP9, IL-1b and its receptor IL-1R1, moderating the excessive DFU inflammatory response, while maintaining biologically beneficial levels of these proteins to promote healing and prevent infection; b) the simultaneous targeting of these relevant proteins will produce a synergetic effect in the inflammation cascade, providing superior efficacy outcomes. Should the main objective of the project is achieved (i.e. show efficacy in animal models of DFU), we would be showing for the first time a potential therapy based on LYTACs, in this case in the context of diabetic ulcers, with potential applications in other types of chronic wound or immune pathologies. In addition to efficacy data, we will be gathering essential knowledge about LYTACs (toxicity, efficacy, mechanism of action, differences with other approaches such as blocking or inhibition which are essential for successful future translation of the novel concept of LYTAC in pharmaceutical development to clinical trials.