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 全球每年有超过 200 万患者接受心脏手术。 急性肾损伤 (CSA-AKI) 是一种严重且严重的并发症，导致住院人数增加 目前，尚无 FDA 批准的 CSA-AKI 治疗方法。 心肺转流术和瓣膜置换术期间流向肾脏的血流减少和缺血 临床和临床前研究已证实，这种情况经常会导致血管和肾小管细胞损伤。 CSA-AKI 患者的血液中存在高水平的心脏毒素、不对称二甲基精氨酸 (ADMA)， 缺血再灌注后动物模型肾脏中的积累可以减少一氧化氮。 (NO) 和肾血流量，并诱导线粒体功能障碍、炎症、细胞死亡和 ADMA 纤维化。 由在肾脏中高表达的二甲基精氨酸二甲氨基水解酶（DDAH）代谢 并显着降低了 AKI 高风险患者（例如既往患有 AKI 的患者）的 AKI 发生率。 此外，肾脏疾病、糖尿病和心脏病等疾病的血清ADMA水平也较高。 与心脏手术相关，如炎症、氧化应激、输血和溶血 促进ADMA生成因此，高水平的ADMA被认为是血液减少的重要介质。 因此，减少病理性 ADMA 代表了一种新的方法。 Vasculonics LLC 正在开发一种基于 DDAH 的生物疗法来治疗 AKI。 减少ADMA。 Vasculonics 对 DDAH 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)，具有所需的药理学特性并可减少体内 ADMA。 初步研究表明，VN-812 可降低高血压大鼠模型的血压。 AKI，VN-812 治疗可减轻炎症并改善肾功能 进一步开发 VN-812 作为一种药物。 临床候选者，Vasculonics 将在本 SBIR 的第一阶段追求以下目标。在目标 1 中，我们将确定。 VN-812 对 ADMA 降低的剂量反应，并选择 ADMA 降低 50% 的剂量以获得疗效 在目标 2 中，我们将确定 VN-812 在肾缺血/再灌注损伤大鼠模型中的疗效。 使用实验设计来测试 VN-812 疗法降低发病率的可行性 在 AKI 之前给药（预防）时，可降低 AKI 的严重程度，并减轻严重程度并改善 在 AKI（治疗）后进行治疗时，Vasculonics 将显示恢复情况。 降低 ADMA 的可行性以及 VN-812 在临床前模型中预防和治疗的功效 AKI 第二阶段的工作将重点关注 IND 的调查，以实现 CMC 和安全性研究。 CSA-AKI 存在商业市场，估计市场超过 10 亿美元。