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

糖尿病足溃疡（DFU）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%。DFU通常以住院治疗结束，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%。尽管高患病率及其对生活质量的重大影响，但尚未批准有效的治疗方法，因此DFU仍然是一种高度未满足的临床疾病。APTADEGRAD旨在使用基于适体的溶酶体靶向嵌合体（LYTAC）治愈糖尿病足溃疡（DFU）的新型一流疗法获得体内概念验证。这些LYTAC将靶向IL-1 β、其受体IL-1 R1和MMP-9进行降解，这些蛋白质已知在糖尿病伤口愈合受损中发挥关键作用。我们的假设是，a）基于适体的LYTAC MoA可以提供提供MMP 9、IL-1b及其受体IL-1 R1的受控的、剂量依赖性的减少的潜力，从而缓和过度的DFU炎症反应，同时保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）这些相关蛋白质的同时靶向将在炎症级联中产生协同效应，提供上级功效结果。如果该项目的主要目标得以实现（即在DFU动物模型中显示出疗效），我们将首次展示基于LYTAC的潜在疗法，在这种情况下，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学中具有潜在的应用。除了疗效数据外，我们还将收集有关LYTAC的基本知识（毒性、疗效、作用机制、与其他方法的差异，如阻断或抑制，这对于未来成功将LYTAC在药物开发中的新概念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.