A Potential DDAH-Biotherapeutic to Preserve Kidney Function in Cardiac Surgery Patients

一种潜在的 DDAH 生物治疗药物可保护心脏手术患者的肾功能

• 批准号: 10080189
• 负责人: Jaipal Singh
• 金额: $ 23.46万
• 依托单位: VASCULONICS, LLC
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10080189
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Aftercare; Animal Model; Arginine; Biological Availability; Biological Response Modifier Therapy; Blood; Blood Circulation; Blood Transfusion; Blood Vessels; Blood flow; Cardiac Catheterization Procedures; Cardiac Output; Cardiac Surgery procedures; Cardiopulmonary Bypass; Cardiovascular Diseases; Cell Death; Chronic Kidney Failure; Clinical Research; Closure by clamp; Complication; Creatinine; DNA Sequence Alteration; Data; Diabetes Mellitus; Dialysis procedure; Direct Lytic Factors; Dose; Drug usage; Endothelium; Epithelial; Epithelium; Exhibits; Experimental Designs; FDA approved; Feasibility Studies; Fibrosis; Functional disorder; Gene Delivery; Gene Expression; Gene Mutation; Gene Proteins; Generations; Health Care Costs; Heart; Heart Diseases; Hemolysis; Histology; Hour; Impairment; In Vitro; Incidence; Indiana; Inflammation; Injury; Injury to Kidney; Investigation; Ischemia; Kidney; Kidney Diseases; Lead; Length of Stay; Measurement; Mediator of activation protein; Microcirculation; Modeling; N,N-dimethylarginine; Nitric Oxide; Operative Surgical Procedures; Oxidative Stress; Pathologic; Pathway interactions; Patient-Focused Outcomes; Patients; Perfusion; Pharmacology; Phase; Plasma; Play; Post-Translational Protein Processing; Postoperative Period; Pre-Clinical Model; Prevention; Procedures; Process; Property; Rattus; Recombinants; Recovery; Renal Blood Flow; Renal dialysis; Renal function; Reperfusion Injury; Reperfusion Therapy; Research; Risk; Risk Factors; Role; Serum; Severities; Small Business Innovation Research Grant; Testing; Therapeutic Intervention; Thromboembolism; Tubular formation; Vascular Endothelium; base; blood pressure reduction; care costs; cell injury; clinical candidate; dimethylargininase; effective intervention; efficacy study; experience; heart valve replacement; high risk; hospital readmission; improved; in vivo; inhibitor/antagonist; injury prevention; kidney preservation; mitochondrial dysfunction; mortality; nephrotoxicity; new therapeutic target; novel; novel strategies; novel therapeutic intervention; preclinical study; prevent; protein degradation; renal ischemia; response; safety study; targeted treatment; treatment response; valve replacement; vascular inflammation; vasoconstriction

Abstract More that 2 million patients worldwide undergo cardiac surgery each year. Cardiac Surgery Associated- Acute Kidney Injury (CSA-AKI) is a serious and significant complication that leads to an increased hospital stay, cost of care, renal dialysis and mortality. Currently, no FDA approved therapy is available for CSA-AKI. Reduced blood flow to the kidney and ischemia during the cardiopulmonary bypass and valve replacement are frequent which can lead to vascular and tubular cell damage. Clinical and preclinical studies have established that high levels of the cardiotoxin, asymmetric dimethyl arginine (ADMA), occur in blood of CSA-AKI patients, and accumulate in the kidney of animal models following ischemia-reperfusion. ADMA can reduce nitric oxide (NO) and renal blood flow, and induce mitochondrial dysfunction, inflammation, cell death and fibrosis. ADMA is metabolized by dimethylarginine dimethylaminohydrolase (DDAH) which is highly expressed in the kidney and dramatically reduced following AKI in rats. Patients with high risk of AKI such as those with preexisting kidney disease, diabetes and heart disease have high serum levels of ADMA. Further, the conditions associated with cardiac surgery such as inflammation, oxidative stress, blood transfusion and hemolysis promote ADMA generation. Thus, high level of ADMA is considered an important mediator of reduced blood flow and renal injury in cardiac surgery patients. Therefore, reduction of pathological ADMA represents a novel therapeutic approach for the treatment of AKI. Vasculonics LLC is developing a DDAH based biotherapy to reduce ADMA. Vasculonics’ research on genetic mutations and protein modifications of DDAH has produced a fully active modified DDAH (VN-812) which exhibits desired pharmacological properties and reduction of ADMA in vivo. Preliminary studies have shown that VN-812 reduced blood pressure in hypertensive rats. In a rat model of AKI, treatment with VN-812 reduced inflammation and improved renal function. To further develop VN-812 as a clinical candidate, Vasculonics will pursue the following aims in Phase I of this SBIR. In Aim 1, we will establish the dose response of VN-812 for ADMA lowering and select the dose for 50% ADMA lowering for efficacy studies. In aim 2, we will determine the efficacy of VN-812 in a rat model of renal ischemia/reperfusion injury using an experimental design that will test the feasibility of VN-812 therapy for reduction in the incidence and severity of AKI when administered prior to AKI (prevention), and reduction in severity and improvement in recovery when administered after AKI (treatment). At the end of Phase I, Vasculonics will have demonstrated the feasibility of lowering ADMA, and efficacy of VN-812 in a preclinical model for prevention and treatment of AKI. Phase II efforts will focus on investigation of IND enabling CMC and safety studies. A significant commercial market exists for CSA-AKI with an estimated market in excess of $1 billion.

抽象的 全球200万患者每年接受心脏手术。心脏手术相关 - 急性肾脏损伤（CSA-AKI）是严重而明显的并发症，导致医院增加 停留，护理成本，肾脏透析和死亡率。目前，CSA-AKI尚无FDA批准的疗法。 在心肺旁路和瓣膜更换期间，血液流动流向肾脏和缺血的流量为 通常会导致血管和结节细胞损伤。临床和临床前研究已经建立 高水平的心脏毒素，不对称的二甲基精氨酸（ADMA）发生在CSA-AKI患者的血液中， 并在缺血再灌注后积聚在动物模型的肾脏中。 ADMA可以减少一氧化氮 （NO）和肾脏血流，并诱导线粒体功能障碍，注射，细胞死亡和纤维化。阿德加 通过二甲基精氨酸二甲基氨基氢化酶（DDAH）代谢，该酶在肾脏中高度表达 在大鼠的AKI之后，大大减少了。患有AKI高风险的患者，例如先前存在的患者 肾脏疾病，糖尿病和心脏病具有高血清ADMA水平。此外，条件 与心脏手术，例如感染，氧化应激，输血和溶血有关 促进ADMA产生。这是高水平的ADMA被认为是血液减少的重要介体 心脏手术患者的流量和肾脏损伤。因此，减少病理ADMA代表了一种新颖 治疗AKI的治疗方法。 Vasculonics LLC正在开发基于DDAH的生物治疗 减少ADMA。 Vasculonics对DDAH的基因突变和蛋白质修饰的研究产生了完全活跃的 修饰的DDAH（VN-812），具有所需的药物特性和体内ADMA的降低。 初步研究表明，VN-812降低了高血压大鼠的血压。在大鼠模型中 AKI，用VN-812的治疗减少了注射和改善的肾功能。进一步发展VN-812 临床候选人，Vasculonics将在该SBIR的第一阶段追求以下目标。在AIM 1中，我们将建立 VN-812的剂量响应用于降低ADMA，并为降低50％ADMA的剂量降低剂量 研究。在AIM 2中，我们将确定VN-812在肾脏缺血/再灌注损伤大鼠模型中的效率 使用实验设计，该设计将测试VN-812疗法的可行性，以减少事件和 在AKI之前给药时AKI的严重程度（预防），并降低了严重程度和改善 在AKI（治疗）后进行恢复。在第一阶段结束时，Vasculonics将证明 在临床前模型中降低ADMA的可行性以及VN-812的效率 aki。第二阶段的努力将集中于IND启用CMC和安全研究的投资。重要的 CSA-Aki的商业市场估计超过10亿美元。