Efficacy and pharmacokinetic assessment of renal-targeted therapy in a pig model of cisplatin induced acute kidney injury.

顺铂诱导的急性肾损伤猪模型中肾脏靶向治疗的疗效和药代动力学评估。

• 批准号: 10384209
• 负责人: Daniel Alan Heller
• 金额: $ 30.58万
• 依托单位: GOLDILOCKS THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-23 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10384209
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Address; Affect; Animal Model; Animals; Attenuated; Biodistribution; Blood Urea Nitrogen; Cisplatin; Clinical; Clinical Drug Development; Clinical Research; Clinical Treatment; Clinical Trials; Complete Blood Count; Complex; Control Animal; Creatinine; Data; Development; Disease; Distal; Dose; Drug Delivery Systems; Drug Kinetics; Dyes; Encapsulated; Epithelial; Etiology; Exhibits; FDA approved; Family suidae; Goals; Histology; Hospital Costs; Hospitalization; Hour; Human; Hypertension; Immunohistochemistry; Injury; Injury to Kidney; International; Investigational Therapies; Ischemia; Kidney; Kidney Diseases; LCN2 gene; Laboratories; Length of Stay; Letters; Mass Spectrum Analysis; Measurement; Measures; Medical; Metabolic; Modeling; Morbidity - disease rate; Multiple Trauma; Mus; Nephrons; Oligonucleotides; Organ; Outcome; Patient Care; Patients; Peptides; Pharmaceutical Preparations; Pharmacological Treatment; Phase; Physiology; Public Health; Publishing; Reactive Oxygen Species; Renal Replacement Therapy; Reperfusion Therapy; Risk; Rodent; Rodent Model; Safety; Serum; Site; Small Business Innovation Research Grant; Specificity; Technology; Testing; Therapeutic; Therapeutic Intervention; Time; Tissues; Toxic effect; Translating; Treatment Efficacy; Tubular formation; Tumor Tissue; United States; Urinalysis; Work; Xenograft procedure; animal data; clinical care; clinical decision-making; clinical translation; economic impact; effective therapy; human disease; immunoregulation; improved; insight; lung small cell carcinoma; mortality; mouse model; nano; nanoparticle; nanoscale; novel; novel therapeutic intervention; novel therapeutics; particle; phenylmethylpyrazolone; porcine model; residence; small molecule; standard measure; systemic toxicity; targeted delivery; targeted treatment; treatment strategy

PROJECT SUMMARY Acute kidney injury (AKI) is a common clinical condition associated with increased morbidity and mortality. AKI accounts for approximately 2% of hospital admissions in the US, and the annual costs for hospital-acquired AKI are approximately $10 billion. Therapeutic interventions for all forms of AKI remain inadequate, in part due to low drug specificity and poor pharmacokinetic profiles. We have developed a novel nanoscale drug delivery platform that selectively targets the proximal tubular epithelium in rodents (Williams, Nano Letters, 2015; Williams, Hypertension, 2018). This strategy localizes drugs up to 26-fold more efficiently in mouse kidneys than any other organ. The particles release their drug cargo within the proximal and distal tubules while exhibiting no toxic effects on the kidneys or other organs. We and our collaborators have successfully treated murine models of both cisplatin-induced AKI (CI-AKI) and ischemia-reperfusion-induced AKI (IR-AKI). Specifically, we administered mesoscale nanoparticles loaded with the reactive oxygen species (ROS) scavenger edaravone, resulting in striking efficacy against a murine CI-AKI model using a dose of edaravone that was approximately 154 times lower than that previously shown to treat AKI systemically in a rodent model (Williams, bioRxiv, 2020). Further, the platform demonstrated effective treatment against IR-AKI in mice via delivery of either an immunomodulatory oligonucleotide (Han, Kidney International, 2020) or a peptide modulator of NF-κB (Han, JCI Insight, 2020). The data presented in our published studies along with preliminary data in this proposal demonstrate that this mesoscale nanoparticle (MNP) platform exhibits exceptional clinical potential. The overall goal of our company is to address the unmet need for treatment strategies for renal diseases by targeting both approved and experimental therapeutic payloads to the kidneys. The objective of this proposal is to evaluate the pharmacokinetic, biodistribution and efficacy of edaravone-encapsulated MNPs in a pig model of cisplatin- induced AKI. We will pursue the following specific aims: Aim 1: Assess Pharmacokinetics and Biodistribution of Edaravone-Loaded MNPs in a Porcine AKI Model. We will evaluate the pharmacokinetics and biodistribution of edaravone-loaded mesoscale nanoparticles in a pig model of AKI. Aim 2: Assess Efficacy and Safety of Edaravone-Loaded MNPs in a Porcine AKI Model. We will determine efficacy and safety of edaravone-MNPs and compare with soluble edaravone in a cisplatin-induced pig AKI model. The outcomes of this Phase I SBIR include an assessment of the biodistribution, pharmacokinetics and efficacy of edaravone-MNPs in pigs as the best characterized large-animal model to approximate human renal physiology. This work will substantially de- risk this technology. It will also allow the company to initiate CMC and IND-enabling studies and will set the stage for planning appropriate clinical trials in AKI patients.

项目概要 急性肾损伤 (AKI) 是一种常见的临床病症，与 AKI 发病率和死亡率增加相关。 约占美国住院人数的 2%，每年医院获得性 AKI 的费用 大约 100 亿美元用于所有形式的 AKI 的治疗干预措施仍然不足，部分原因是 我们开发了一种新型纳米级药物输送。 选择性靶向啮齿动物近端肾小管上皮的平台（Williams，Nano Letters，2015； Williams，Hypertension，2018）。这种策略将药物定位在小鼠肾脏中的效率比其他策略高 26 倍。 颗粒在近端和远端小管内释放药物，但不表现出任何其他器官。 对肾脏或其他器官的毒性作用我们和我们的合作者已经成功治疗了小鼠模型。 具体来说，我们研究了顺铂诱导的 AKI (CI-AKI) 和缺血再灌注诱导的 AKI (IR-AKI)。 施用负载活性氧（ROS）清除剂依达拉奉的中尺度纳米颗粒， 使用剂量约为 比之前在啮齿动物模型中系统治疗 AKI 的效果低 154 倍（Williams，bioRxiv，2020）。 此外，该平台还证明了通过递送任一药物可有效治疗小鼠 IR-AKI。 免疫调节寡核苷酸（Han，Kidney International，2020）或 NF-κB 肽调节剂（Han，JCI Insight，2020）。我们发表的研究中提供的数据以及本提案中的初步数据。 证明这种中尺度纳米颗粒（MNP）平台表现出非凡的临床潜力。 我们公司的目标是通过针对肾脏疾病治疗策略来满足未满足的需求 该提案的目的是评估肾脏的批准和实验性治疗有效负载。 依达拉奉封装的 MNP 在顺铂猪模型中的药代动力学、生物分布和功效 我们将追求以下具体目标： 目标 1：评估 AKI 的药代动力学和生物分布。 猪 AKI 模型中加载依达拉奉的 MNP 我们将评估其药代动力学和生物分布。 在 AKI 猪模型中加载依达拉奉的中尺度纳米粒子 目标 2：评估 AKI 的功效和安全性。 猪 AKI 模型中加载依达拉奉的 MNP 我们将确定依达拉奉 MNP 的有效性和安全性。 并与顺铂诱导的猪 AKI 模型中的可溶性依达拉奉进行比较。 包括对依达拉奉 MNP 在猪体内的生物分布、药代动力学和功效进行评估 这项工作将极大地简化模拟人类肾脏生理学的特征的大型动物模型。 它还将使公司能够启动 CMC 和 IND 支持研究，并奠定基础。 用于规划 AKI 患者的适当临床试验。