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

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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.