Urocortin-2 Gene Transfer for Type 1 Diabetes and Associated LV Dysfunction

ABSTRACT TypeDiabetes MellitusT DMaffectsmillion patients in US withnew patients annuallyLifespan is shortenedyearsdue to kidney and heart diseaseTight glucose control reduces microvascular complications and adverse cardiovascular eventsInsulin therapy is essential for such patientsbut has shortcomingsaonlyinpatients achieve targeted glucose controlHbA c andltbaggressive insulin therapy increases episodic hypoglycemiawhich itself shortens lifecmost T DM patients develop insulin resistanceCardiovascular risk isfold higher in T DM patients with insulin resistance vs those with normal insulin resistanceWe propose to test a new approach to address these shortcomings in T DM therapyRecent clinical trials have tested non insulin agents in combination with insulin in T DMto improve glycemic control and reduce insulin requirementsIn generalthese trials show lower HbA c and insulin needsbut unacceptable side effectsAn ideal adjunct to insulin wouldreduce insulin needs and weight gainreduce HbA crequire infrequent administrationandfavorably affect heart functionOur data in mice indicate that urocortinUCngene transfer fulfills these criteria in insulin resistant miceand we recently have discovered that UCngene transfer normalizes glycemic controlreduces retinopathyimproves cardiac functionand reduces mortality in a murine model of T DMWe have shown the utility of intravenous delivery of a vector encoding a transgene with paracrine actions that increases insulin sensitivity and release in diabetesThis strategy enables patients to be treated during an office visit by a single injection of the vectorIt would eliminate the need for repeated administrationreduce costs and increase complianceThe best vector to achieve these goals is adeno associated virus typeAAVencoding UCnThe goals of this proposal are to develop and optimally refine this approach to be used concomitantly with insulin in patients with T DMT DM is a major risk factor for several prevalent life altering and life terminating diseases that are the focus of NHLBIperipheral vascular diseasestrokemyocardial infarctionand heart failureThe discovery and development of more effective therapies for T DM is imperativeand is likely to reduce the prevalence of the cardiovascular complications associated with T DMThe goal of the current proposal is to test this new approach NARRATIVE We propose to develop a method to treat patients with typediabetes mellitusT DMusing an intravenous injection of a gene therapy vector encoding a peptide that increases glucose disposal and thereby increases glycemic controlThe peptide is called urocortinand it has favorable effects on the heart in addition to its favorable effects in diabetesso will be useful in patients with diabetic related heart diseaseIn animal studies of typediabetesa single intravenous injection of the vector normalizes blood glucosereverses kidney diseasereduces mortalityand increases heart function