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

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R43DK125142-01A1
Agency Tracking Number: R43DK125142
Amount: $234,583.00
Phase: Phase I
Program: SBIR
Solicitation Topic Code: 300
Solicitation Number: PA19-272
Solicitation Year: 2019
Award Year: 2020
Award Start Date (Proposal Award Date): 2020-09-01
Award End Date (Contract End Date): 2021-08-31
Small Business Information
Indianapolis, IN 46202-1218
United States
DUNS: 080789952
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: Yes
Principal Investigator
 (404) 775-4727
Business Contact
Phone: (217) 819-7387
Research Institution

AbstractMore 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.Project Narrative: Up to 30% of the patients undergoing cardio-pulmonary bypass surgery and heart valve
replacement experience acute kidney injury (AKI). The cardiac surgery associated-AKI (CSA-AKI) significantly
increase hospital stay, re-admissions, healthcare cost and mortality. There is no FDA approved therapy for
AKI. Vasculonics is developing a novel approach to prevent and treat CSA-AKI, and improve patient outcome.

* Information listed above is at the time of submission. *

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