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

摘要 全世界每年有200多万患者接受心脏手术。心脏手术相关- 急性肾损伤（CSA-AKI）是一种严重且显著的并发症，导致住院时间增加 住院时间、护理费用、肾透析和死亡率。目前，没有FDA批准的疗法可用于CSA-AKI。 在心肺转流术和瓣膜置换术期间， 频繁，可导致血管和肾小管细胞损伤。临床和临床前研究已经建立了 CSA-AKI患者血液中出现高水平的心脏毒素，不对称二甲基精氨酸（ADMA）， 并在缺血-再灌注后的动物模型的肾脏中积累。ADMA可以减少一氧化氮 (NO)和肾血流，并诱导线粒体功能障碍、炎症、细胞死亡和纤维化。ADMA 通过在肾脏中高度表达的二甲基精氨酸二甲氨基水解酶（DDAH）代谢 并且在大鼠阿基后显著降低。阿基高风险患者，如既往存在 肾病、糖尿病和心脏病具有高血清ADMA水平。此外，条件 与心脏手术相关的炎症、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。 心脏手术患者的血流和肾损伤。因此，减少病理性ADMA代表了一种新的 阿基的治疗方法。Vasculonics LLC正在开发一种基于DDAH的生物疗法， 减少ADMA。 Vasculonics对DDAH基因突变和蛋白质修饰的研究已经产生了一种完全活性的 修饰的DDAH（VN-812），其表现出所需的药理学性质和体内ADMA的减少。 初步研究表明，VN-812可降低高血压大鼠的血压。的大鼠模型中 用VN-812治疗阿基减少炎症并改善肾功能。为了进一步开发VN-812作为 作为临床候选人，Vasculonics将在本SBIR的第I阶段实现以下目标。在目标1中，我们将 VN-812降低ADMA的剂量反应，并选择降低50% ADMA的有效剂量 问题研究在目的2中，我们将确定VN-812在肾缺血/再灌注损伤的大鼠模型中的功效 使用实验设计，该实验设计将测试VN-812疗法用于降低发病率的可行性， 在阿基之前给药时阿基的严重程度（预防），以及严重程度的降低和 阿基（治疗）后恢复。在第一阶段结束时，Vasculonics将证明 降低ADMA的可行性，以及VN-812在临床前模型中预防和治疗 阿基第二阶段的工作将集中在研究IND使CMC和安全性研究。显著 CSA-AKI存在商业市场，估计市场超过10亿美元。

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.