Therapy of transplantation-induced oxidative injury using polymeric antioxidants

描述(由申请人提供)：肾移植手术中的缺血再灌注(I/R)损伤是导致免疫激活和移植物排斥反应的氧化应激的原因。我们正在开发一种抗氧化疗法，我们已经证明，在各种体外模型以及肾脏、心脏和肢体损伤的I/R模型中，这种疗法在改善氧化应激造成的损害方面非常有效。重要的是，在任何模型中都没有观察到毒性的迹象。然而，我们将进行全面的安全评估，作为这笔赠款的一个重要组成部分。该产品是聚草酸-香草醇(VA)共聚物粒子的分散体。聚合物被过氧化氢降解(从而降低了局部ROS的浓度)，产生了VA，这本身就是一种有效的抗氧化剂。我们将这些疗法称为抗氧化剂聚合物前体药物，或APP“。它们的聚合物化学和生物学被很好地理解，并表明其具有极好的安全性。它们特定部位的抗氧化活性仅在氧化应激部位产生，尽管全身给药，没有昂贵和略微有效的靶向分子。这提高了APP的安全性和有效性。事实上，单个直径500 nm的APP”颗粒提供了缓解~1011个ROS分子的能力，并且只有在ROS存在的情况下才有效，即APP的活性是自我限制的。到目前为止，我们已经生产了APP-103(我们的主要APP产品)，达到了临床前工作所需的规模，在体外证明了其抗氧化和抗炎活性，测定了其释放动力学，并在小鼠肢体I/R模型中展示了剂量依赖的有效性、有效性和体内位置特异性，在肾脏、肝脏和心脏I/R模型中的有效性，在体内对抗阿霉素引起的心脏和肝脏毒性的有效性，以及高剂量的基本安全性。这些研究的详细内容见研究策略一节。我们的首要目标是将这一有希望的实验室疗法推向临床。为此，我们将：扩大APP-103的生产规模，开发颗粒表型和功能的QA/QC分析，并证明缩放颗粒在体内外的等效性，测定健康小鼠的MTD，确定大鼠I/R模型的最低预期生物学效应水平(MABEL)，在大鼠肾移植研究中展示疗效，以及完成临床前安全性测试，所有这些最终都将提交给APP-103的IND。

DESCRIPTION (provided by applicant): Ischemia-reperfusion (I/R) injury during renal transplantation surgery is responsible for oxidative stresses which result in immune activation and graft rejection. We are developing an antioxidative therapy that we have already shown to be highly efficacious in ameliorating damage from oxidative stress in various in vitro models as well as I/R models of kidney, heart, and limb injury. Importantly, no signs of toxicity have been observed in any model. We will, however, undertake a comprehensive safety evaluation as a key component of this grant. The product is a dispersion of polyoxalate-vanillyl alcohol (VA) copolymer particles. The polymer is degraded by hydrogen peroxide (thereby reducing the local concentration of ROS) yielding VA, a potent antioxidant in its own right. We refer to these therapies as Antioxidant Polymer Prodrugs, or APPs". Their polymer chemistry and biology are well understood and indicative of an excellent safety profile. Their site-specific antioxidative activity is only produced at the sites of oxidative stress, despite systemic administration and without expensive and marginally effective targeting molecules. This increases APPs' safety profile and efficacy. Indeed, a single 500 nm diameter APP" particle provides the ability to mitigate ~1011 ROS molecules, and will only be active in the presence of ROS, i.e. APP activity is self-limiting. To date, we have: produced APP-103 (our lead APP product) at the scale necessary for preclinical work, demonstrated its antioxidative and anti-inflammatory activity in vitro, determined its release kinetics, and demonstrated dose-dependent efficacy, efficacy and site-specificity in vivo in a murine limb I/R model, efficacy in kidney, hepatic and cardiac I/R models, efficacy against doxorubicin-induced cardio and hepato-toxicities in vivo, and a basic safety profile at high dose. Details of these studies are presented in the Research Strategy section. Our overarching goal is to move this promising laboratory therapy into the clinic. To do this we will: scale up APP-103 production, develop QA/QC assays for particle phenotype and function and demonstrate equivalence of scaled particles in vitro and in vivo, determine MTD in healthy mice, determine minimum anticipated biological effect level (MABEL) in rat I/R model, demonstrate efficacy in rat renal transplant studies, and complete preclinical safety testing, all culminating in an IND submission for APP-103.