Mitigation of Acute Kidney Injury (AKI) using the polymer prodrug, APP-103TM

使用聚合物前药 APP-103TM 缓解急性肾损伤 (AKI)

• 批准号: 10223280
• 负责人: Jake Reder
• 金额: $ 74.72万
• 依托单位: CELDARA MEDICAL, LLC
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10223280
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Alcohols; Animal Model; Animals; Anti-Inflammatory Agents; Antioxidants; Biology; Body Fluids; Caliber; Cardiovascular Surgical Procedures; Chemistry; Chronic; Chronic Kidney Failure; Clinical; Closure by clamp; Critical Illness; Development; Dose; Event; Fluid Balance; Guidelines; Healthcare Systems; Heart; Heart Injuries; Hour; Hydrogen Peroxide; Incidence; Inflammation; Injury; Injury to Kidney; Intervention; Kidney; Kidney Transplantation; Lead; Length; Length of Stay; Letters; Life; Modeling; Operative Surgical Procedures; Organ; Outcome; Oxidative Stress; Patients; Pharmaceutical Preparations; Pharmacology Study; Phase; Polymer Chemistry; Polymers; Positioning Attribute; Preparation; Process; Prodrugs; Production; Program Development; Rattus; Reactive Oxygen Species; Renal function; Reperfusion Injury; Reporting; Role; Safety; Savings; Site; Small Business Innovation Research Grant; Syndrome; Therapeutic; Therapeutic Effect; Toxic effect; Work; analytical method; animal efficacy; cGMP production; clinical application; clinical outcome measures; cohort; comorbidity; copolymer; efficacy study; graft function; health care economics; improved; insight; interest; kidney dysfunction; limb injury; meetings; mortality; nanoparticle; novel; oxidative damage; particle; porcine model; pre-clinical; preclinical development; preclinical study; prevent; process optimization; renal ischemia; success

Project Summary Acute Kidney Injury (AKI) is common in hospitalized patients after severe illness or following major surgeries, such as cardiovascular surgery. The incidence of AKI in critically ill patients is greater than 40%. Patients who have an AKI event have poor long-term outcomes including increased debilitating comorbidities such as chronic kidney disease and increased mortality. Ischemia/reperfusion injury (IRI), an unavoidable consequence of cardiovascular surgery, is a known cause of AKI. IRI is partially the result of the formation of reactive oxygen species (ROS) in the absence of sufficient antioxidative moieties, and can lead to the induction of inflammation. There is currently no clinically available therapeutic treatment to prevent or treat AKI, which leaves a large cohort of suffering patients and a high burden on our healthcare system. Our product, APP-103™, consists of effective anti-oxidant and anti-inflammatory copolymer nanoparticles that have previously been demonstrated to be highly effective in ameliorating damage from oxidative stress in several IRI models of kidney, heart, limb injury, and renal transplantation. APP-103™ is a dispersion of polyoxalate-vanillyl alcohol (VA) copolymer particles that is degraded by hydrogen peroxide, thereby reducing the local concentration of ROS and yielding anti-inflammatory VA. The polymer chemistry and biology of APP-103 is well understood and indicative of an excellent safety profile. While easily administered systemically, it offers site-specific anti-oxidative and anti-inflammatory therapy without expensive and marginally effective targeting molecules. A single 500 nm diameter APP™ particle provides the ability to mitigate ~1011 ROS molecules, and is activated only in the presence of ROS, i.e. APP activity is self-limiting. To date, we have been able to produce APP-103™ at the scale necessary for preclinical work, and are advancing through IND-enabling studies with no toxicity. We have also demonstrated efficacy in pre-clinical AKI models. The purpose of this proposal is to provide mechanistic insight of APP-103 in kidney IRI, demonstrate proof of concept in a large animal model of AKI, and then advance APP-103™ from lab manufacturing through completion of IND-enabling studies. The milestone of ultimate success will be the submission of an IND in order to bring this exceptionally promising therapy into clinical application.

项目摘要 急性肾损伤(AKI)常见于重症或急性肾损伤住院患者 在大手术之后，如心血管手术。急性肾损伤在危重患者中的发生率 患病患者占40%以上。发生AKI事件的患者长期预后较差 结果包括增加衰弱的合并症，如慢性肾脏疾病 并增加了死亡率。缺血再灌注损伤(IRI)，这是一种不可避免的后果 心血管手术，是AKI的已知原因。IRI部分是形成的结果 在缺乏足够的抗氧化性部分的情况下，活性氧物种(ROS)的数量，以及 会导致炎症的诱发。目前还没有临床可用的 预防或治疗AKI的治疗性治疗，这会留下大量的痛苦 这给我们的医疗保健系统带来了沉重的负担。 我们的产品APP-103™含有有效的抗氧化剂和抗炎成分 先前已被证明在治疗中高度有效的共聚纳米粒 改善几种肾脏、心脏、肢体IRI模型的氧化应激损伤 损伤和肾移植。APP-103™是聚草酸-香草醇的分散体 (VA)可被过氧化氢降解的共聚粒子，从而减少局部 ROS的浓度和产生抗炎的VA。聚合物化学和 APP-103的生物学特性得到了很好的理解，并显示出极好的安全性。而当 它易于全身服用，具有特定部位的抗氧化和抗炎作用。 治疗不需要昂贵和略微有效的靶向分子。单个500纳米 直径APP™颗粒提供了缓解~1011ROS分子的能力，并且是 只有在ROS存在的情况下才会激活，即应用程序活动是自我限制的。 到目前为止，我们已经能够以临床前所需的规模生产APP-103™ 工作，并正在无毒性地通过启用IND的研究。我们还有 在临床前AKI模型中证明了有效性。这项建议的目的是 提供APP-103在肾脏IRI中的机械性见解，演示概念验证 在AKI的大型动物模型中，然后从实验室制造的APP-103™ 通过完成支持IND的研究。最终成功的里程碑将是 提交IND的意见书，以便带来这种特别有希望的疗法 进入临床应用。