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

ABSTRACT Type-1 Diabetes Mellitus (T1DM) affects 1.25 million patients in US with 40,000 new patients annually. Lifespan is shortened 11-13 years, due to kidney and heart disease. Tight glucose control reduces microvascular complications and adverse cardiovascular events. Insulin therapy is essential for such patients, but has shortcomings: a) only 1 in 3 patients achieve targeted glucose control (HbA1c lt7%); b) aggressive insulin therapy increases episodic hypoglycemia, which itself shortens life; c) most T1DM patients develop insulin resistance. Cardiovascular risk is 2.5-fold higher in T1DM patients with insulin resistance vs those with normal insulin resistance. We propose to test a new approach to address these shortcomings in T1DM therapy. Recent clinical trials have tested non-insulin agents in combination with insulin in T1DM, to improve glycemic control and reduce insulin requirements. In general, these trials show lower HbA1c and insulin needs, but unacceptable side-effects. An ideal adjunct to insulin would: 1) reduce insulin needs and weight gain; 2) reduce HbA1c; 3) require infrequent administration; and 4) favorably affect heart function. Our data in mice indicate that urocortin 2 (UCn2) gene transfer fulfills these criteria in insulin resistant mice, and we recently have discovered that UCn2 gene transfer normalizes glycemic control, reduces retinopathy, improves cardiac function, and reduces mortality in a murine model of T1DM. We have shown the utility of intravenous delivery of a vector encoding a transgene with paracrine actions that increases insulin sensitivity and release in diabetes. This strategy enables patients to be treated during an office visit by a single injection of the vector. It would eliminate the need for repeated administration, reduce costs and increase compliance. The best vector to achieve these goals is adeno-associated virus type 8 (AAV8), encoding UCn2.The goals of this proposal are to develop and optimally refine this approach to be used concomitantly with insulin in patients with T1DM. T1DM is a major risk factor for several prevalent life-altering and life-terminating diseases that are the focus of NHLBI: peripheral vascular disease, stroke, myocardial infarction, and heart failure. The discovery and development of more effective therapies for T1DM is imperative, and is likely to reduce the prevalence of the cardiovascular complications associated with T1DM. The goal of the current proposal is to test this new approach.