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，约25%的患者发生，5年复发率约为65%。DFUs通常以住院治疗告终，高达60%的病例截肢。DFU相关的死亡率在12个月内为5%，5年后上升至42%。尽管DFU的患病率很高，对生活质量有重大影响，但目前尚无有效的治疗方法，因此DFU仍然是一个高度未满足的临床疾病。APTADEGRAD旨在获得一种新型的，一流的治疗方法的体内概念验证，该疗法使用基于适配体的溶酶体靶向嵌合体（LYTACs）来治疗糖尿病足溃疡（DFUs）。这些lytac将靶向IL-1ß，其受体IL-1R1和MMP-9降解，已知这些蛋白质在糖尿病伤口愈合受损中起关键作用。我们的假设是：a)基于适配体的LYTACs MoA可能提供一种可控的、剂量依赖性的MMP9、IL-1b及其受体IL-1R1的减少，减缓过度的DFU炎症反应，同时维持这些蛋白质的生物学有益水平，以促进愈合和预防感染；B)同时靶向这些相关蛋白将在炎症级联中产生协同作用，提供优越的疗效结果。如果该项目的主要目标得以实现（即在DFU动物模型中显示疗效），我们将首次展示基于LYTACs的潜在治疗方法，在糖尿病溃疡的背景下，在其他类型的慢性伤口或免疫病理中具有潜在的应用。除了功效数据外，我们还将收集LYTAC的基本知识（毒性、功效、作用机制、与其他方法（如阻断或抑制）的差异），这对于未来将LYTAC的新概念从药物开发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.