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 andlt;7%); 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.NARRATIVE
We propose to develop a method to treat patients with type 1 diabetes mellitus (T1DM) using an intravenous
injection of a gene therapy vector encoding a peptide that increases glucose disposal and thereby increases
glycemic control. The peptide is called urocortin 2 and it has favorable effects on the heart in addition to its
favorable effects in diabetes, so will be useful in patients with diabetic-related heart disease. In animal studies
of type 1 diabetes, a single intravenous injection of the vector normalizes blood glucose, reverses kidney
disease, reduces mortality, and increases heart function.