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.

项目总结 急性肾损伤(AKI)是一种常见的临床症状，与发病率和死亡率的增加有关。阿基 约占美国住院人数的2%，医院获得的AKI的年度成本 约为100亿美元。对所有形式的AKI的治疗干预仍然不足，部分原因是 药物特异性低，药代动力学特征差。我们已经开发出一种新型的纳米级药物递送 选择性靶向啮齿动物近端肾小管上皮的平台(Williams，Nano Letters，2015； 威廉姆斯，高血压，2018年)。这一策略将药物在小鼠肾脏中的定位效率提高了26倍 任何其他器官。这些微粒在近端和远端小管内释放其药物货物，而不显示 对肾脏或其他器官的毒性影响。我们和我们的合作者已经成功地治疗了小鼠模型 顺铂诱导AKI(CI-AKI)和缺血再灌注性AKI(IR-AKI)。具体来说，我们 给予中尺度纳米颗粒负载活性氧物种(ROS)清除剂依达拉奉， 导致对小鼠CI-AKI模型的显著疗效，使用剂量约为 比之前在啮齿动物模型中系统治疗AKI的结果低154倍(Williams，BioRxiv，2020)。 此外，该平台在小鼠身上展示了通过传递一个或多个 免疫调节性寡核苷酸(HAN，肾国际，2020年)或核因子-κB的多肽调节剂(HAN，JCI 洞察，2020)。在我们已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)平台显示出非凡的临床潜力。整体而言 我们公司的目标是解决未得到满足的肾脏疾病治疗策略的需求，目标是 经批准的和实验性的肾脏治疗有效载荷。这项建议的目标是评估 依达拉奉MNPs在猪顺铂模型中的药代动力学、生物分布和疗效 诱导AKI。我们将追求以下具体目标：目标1：评估阿司匹林的药代动力学和生物分布 在猪AKI模型中加载依达拉奉MNPs。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中尺度纳米颗粒。目标2：评估药物的有效性和安全性 在猪AKI模型中加载依达拉奉MNPs。我们将测定依达拉奉-MNPs的疗效和安全性 并在顺铂诱导的猪AKI模型中与可溶性依达拉奉进行比较。第一阶段SBIR的结果 包括评估依达拉奉-MNPs在猪体内的生物分布、药代动力学和疗效 最适合人类肾脏生理学的大型动物模型。这项工作将大大降低- 冒着这个技术的风险。它还将允许该公司启动CMC和IND支持研究，并将为 计划对AKI患者进行适当的临床试验。