Therapy of transplantation-induced oxidative injury using polymeric antioxidants

使用聚合抗氧化剂治疗移植引起的氧化损伤

• 批准号: 8951662
• 负责人: MICHAEL W FANGER
• 金额: $ 74.5万
• 依托单位: CELDARA MEDICAL, LLC
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8951662
• 关键词: Alcohols; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Biological; Biological Assay; Biology; Budgets; Caliber; Clinic; Clinical; Development Plans; Disease; Dose; Doxorubicin; Evaluation; Goals; Graft Rejection; Grant; Heart; Hepatic; Hydrogen Peroxide; In Vitro; Injury; Ischemia; Kidney; Kidney Transplantation; Kinetics; Laboratories; Lead; Life; Limb structure; Modeling; Mus; Myocardial Ischemia; Operative Surgical Procedures; Organ Transplantation; Oxidative Stress; Phase; Phenotype; Polymer Chemistry; Polymers; Procedures; Process; Prodrugs; Production; Rattus; Reactive Oxygen Species; Reperfusion Injury; Reperfusion Therapy; Research; Safety; Site; Specificity; Tissues; Toxic effect; Transplantation; Work; base; copolymer; immune activation; in vitro Model; in vitro activity; in vivo; limb injury; particle; pre-clinical; preclinical safety; public health relevance; renal ischemia; safety testing; scale up

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.

描述（由申请人提供）：肾移植手术期间的缺血-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，该疗法在改善氧化应激损伤方面非常有效。重要的是，在任何模型中均未观察到毒性体征。然而，我们将进行全面的安全评估，作为这笔赠款的关键组成部分。该产品是聚碳酸酯-香草醇（VA）共聚物颗粒的分散体。聚合物被过氧化氢降解（从而降低ROS的局部浓度），产生VA，VA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药或APP。它们的聚合物化学和生物学已被充分理解，并表明具有优异的安全性。它们的位点特异性抗氧化活性仅在氧化应激位点产生，尽管全身给药并且没有昂贵且边缘有效的靶向分子。这增加了APP的安全性和有效性。事实上，单个500 nm直径的APP颗粒提供了减轻~1011个ROS分子的能力，并且仅在ROS存在下才有活性，即APP活性是自限性的。迄今为止，我们已经：生产的APP-103（我们的主要APP产品）在临床前工作所需的规模下，证明了其体外抗氧化和抗炎活性，测定了其释放动力学，并证明了剂量依赖性功效，在鼠肢体I/R模型中的体内功效和位点特异性，在肾脏、肝脏和心脏I/R模型中的功效，体内对抗多柔比星诱导的心脏和肝脏毒性的功效，和高剂量下的基本安全性。这些研究的详细信息见研究策略部分。我们的首要目标是将这种有前途的实验室疗法推向临床。为此，我们将：扩大APP-103的生产，开发颗粒表型和功能的QA/QC测定，并证明体外和体内缩放颗粒的等效性，确定健康小鼠中的MTD，确定大鼠I/R模型中的最低预期生物效应水平（美宝），证明大鼠肾移植研究中的功效，并完成临床前安全性测试，所有这些最终导致APP-103的IND提交。