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: 9920348
• 负责人: Brandy Lynn Houser
• 金额: $ 99.86万
• 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 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9920348
• 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; Family suidae; 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; Outcome Measure; 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; cohort; comorbidity; copolymer; efficacy study; graft function; health care economics; improved; insight; interest; kidney dysfunction; limb injury; meetings; mortality; nanoparticle; novel; oxidative damage; particle; 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（阿基）常见于严重疾病后住院的患者， 在大手术之后，例如心血管手术。危重患者阿基的发生率 患病率超过40%。发生阿基事件的患者的长期 结局包括使人衰弱的合并症增加，如慢性肾脏疾病 和死亡率的增加。缺血/再灌注损伤（IRI）是缺血/再灌注不可避免的后果 心血管手术是阿基的已知原因。IRI部分是形成的结果 活性氧（ROS）在缺乏足够的抗氧化部分，和 会导致炎症的产生目前临床上没有可用的 预防或治疗阿基的治疗性治疗，这使得大量患有AKI的患者 患者和我们的医疗保健系统的高负担。 我们的产品APP-103™含有有效的抗氧化和抗炎成分， 先前已经证明的共聚物纳米颗粒在以下方面高度有效： 改善肾脏、心脏、肢体的几种IRI模型中的氧化应激损伤 损伤和肾移植。APP-103™是聚碳酸酯-香草醇的分散体 (VA)通过过氧化氢降解的共聚物颗粒，从而减少局部的 浓度的ROS和产生抗炎VA。聚合物化学和 APP-103的生物学被很好地理解，并且表明了优异的安全性特征。而 易于全身给药，它提供了特定部位的抗氧化和抗炎 没有昂贵的和边缘有效的靶向分子的治疗。单个500 nm 直径的APP™颗粒提供了减轻~1011个ROS分子的能力， 仅在ROS存在下激活，即APP活性是自限性的。 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，并正在推进通过IND使研究无毒性。我们还 在临床前阿基模型中证实了疗效。这项建议的目的是 提供APP-103在肾脏IRI中的机制见解，证明概念验证 在阿基大型动物模型中，然后从实验室生产的先进APP-103™ 通过完成国家发展研究。最终成功的里程碑将 提交IND，以便将这种非常有前途的疗法 临床应用。