Small Molecule Erythropoietin Receptor Agonists for the Treatment of Acute Kidney

小分子促红细胞生成素受体激动剂治疗急性肾病

• 批准号: 8592009
• 负责人: Juha Punnonen
• 金额: $ 22.76万
• 依托单位: STATEGICS, INC.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2014-10-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8592009
• 关键词: Acute; Acute Renal Failure with Renal Papillary Necrosis; Admission activity; Adverse effects; Adverse event; Agonist; Animal Model; Biochemical; Blood Chemical Analysis; Blood Urea Nitrogen; Cell Culture Techniques; Cell Line; Cells; Cisplatin; Clinical; Clinical Research; Complement; Complication; Creatinine; Development; Disease; Doctor of Philosophy; Dose; End stage renal failure; Erythropoietin; Erythropoietin Receptor; Event; Future; Goals; Hematoxylin and Eosin Staining Method; Hospitals; Human; Impairment; In Vitro; Injury; Intensive Care Units; Interleukin-6; Intraperitoneal Injections; Ischemia; Kidney; Kidney Failure; Lead; Letters; Measures; Modeling; Nephrology; Neurons; Patients; Peptides; Peroxides; Phase; Phosphorylation; Property; Proteins; Rattus; Reaction Time; Receptor Activation; Receptor Signaling; Renal function; Reperfusion Therapy; Research Design; Risk; Rodent; Safety; Series; Signal Transduction; Small Business Innovation Research Grant; System; TNF gene; Testing; Therapeutic; Tissue Stains; Tissues; Toxic effect; Tubular formation; Universities; base; cell injury; cytokine; cytotoxic; effective therapy; improved; in vivo; inflammatory marker; kidney cell; mimetics; nephrotoxicity; partial recovery; pre-clinical; preclinical study; programs; prophylactic; protective effect; public health relevance; receptor; recombinant human erythropoietin; research clinical testing; small molecule

DESCRIPTION (provided by applicant): Acute kidney injury (AKI) leads to a sudden impairment of renal function. The effects of AKI may be transient followed by full or partial recovery, but often progress to more severe renal insufficiency or end-stage renal disease. There are no approved therapies available. Previous studies support the view that, at sufficiently high doses, recombinant human (rh) erythropoietin (EPO) protects kidneys in animal models of AKI. However, high doses are needed to achieve renal protection in preclinical studies, 5,000 IU/kg daily, because rhEPO does not efficiently access the extravascular system. The currently recommended doses of rhEPO in clinical settings are far lower (maximum to 900 IU/kg weekly), suggesting that dosing rhEPO at levels required to provide renal protection are not therapeutically viable. Consistent with this notion, the first clinical studies testing rhEPO in AK have provided mixed results, supporting the conclusion that more effective therapies are needed. RhEPO also associates with adverse effects due to its erythropoietic activity increasing the risk of thrombotic events. STATegics is focused on the discovery and development of small molecule cytokine mimetics and has identified non-erythropoietic EPO receptor (EPOR) agonists with potent tissue-protective activity. Using the human proximal tubule cell line HK-2, we find that these compounds activate EPOR and improve survival of the kidney cells in vitro. In addition, our studies indicate protective effects of the compounds on kidney function following chemically-induced AKI in vivo. Potent cytoprotective effects were also observed in rat and human neurons, illustrating broadly protective effects of these small molecules against cytotoxic challenges. In vitro safety assessment did not identify any safety concerns or off-target effects, and the compounds were well tolerated in an initial tolerability study in vivo. Importantly, no erythropoietic activity was observed at cytoprotective concentrations, in vitro or in vivo, suggesting a reduced risk of thrombotic events in vivo when compared to rhEPO. This Phase I program aims to establish a proof-of-concept for tissue- protective, non-erythropoietic small molecule erythropoietin EPOR agonists as potential disease-modifying agents in the treatment of AKI. The aim of the proposed studies is to evaluate and rank the protective effects of two promising compounds in this series using primary human and rat kidney cells in vitro and to test the ability of the most promising compound to protect rats from cisplatin-induced AKI in vivo. If the compound's kidney protective effects can be confirmed, our aim will be to expand into additional models of kidney injury, such as ischemia-reperfusion models. The latter studies would be the subject of a future Phase II application, which would also include more thorough assessment of the compounds' safety in vitro and in vivo. Our long- term goal is to advance the lead compound into clinical testing for the treatment of AKI.

描述（由申请方提供）：急性肾损伤（阿基）导致肾功能突然受损。阿基的影响可能是短暂的，随后完全或部分恢复，但通常进展为更严重的肾功能不全或终末期肾病。目前尚无获批的治疗方法。以前的研究支持这样的观点，即在足够高的剂量下，重组人（rh）促红细胞生成素（EPO）在阿基动物模型中保护肾脏。然而，在临床前研究中需要高剂量以实现肾保护，每天5，000 IU/kg，因为rhEPO不能有效地进入血管外系统。目前在临床环境中推荐的rhEPO剂量要低得多（每周最高900 IU/kg），这表明以提供肾保护所需的水平给药rhEPO在治疗上是不可行的。与这一观点相一致的是，在AK中测试rhEPO的第一个临床研究提供了混合的结果，支持需要更有效的治疗的结论。由于其红细胞生成活性增加了血栓形成事件的风险，RhEPO还与不良反应有关。STATegics专注于小分子细胞因子模拟物的发现和开发，并已鉴定出具有有效组织保护活性的非红细胞生成EPO受体（EPOR）激动剂。使用人近曲小管细胞系HK-2，我们发现这些化合物激活EPOR并提高体外肾细胞的存活率。此外，我们的研究表明，在体内化学诱导的阿基后，化合物对肾功能具有保护作用。在大鼠和人类神经元中也观察到了有效的细胞保护作用，说明了这些小分子对细胞毒性挑战的广泛保护作用。体外安全性评估未发现任何安全性问题或脱靶效应，并且化合物在体内初始耐受性研究中耐受良好。重要的是，在体外或体内的细胞保护浓度下没有观察到红细胞生成活性，表明与rhEPO相比，体内血栓形成事件的风险降低。该I期项目旨在建立组织保护性、非红细胞生成性小分子促红细胞生成素EPOR激动剂作为治疗阿基的潜在疾病调节剂的概念验证。拟议研究的目的是使用体外原代人和大鼠肾细胞评价和排名该系列中两种有前途的化合物的保护作用，并测试最有前途的化合物保护大鼠免受顺铂诱导的阿基的能力。如果该化合物的肾脏保护作用能够得到证实，我们的目标将是扩展到其他肾脏损伤模型，如缺血再灌注模型。后一项研究将是未来第二阶段应用的主题，其中还将包括对化合物在体外和体内的安全性进行更彻底的评估。我们的长期目标是推进先导化合物进入治疗阿基的临床试验。