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

摘要 在美国，1型糖尿病(T1 DM)每年影响125万患者，新增患者4万人。 由于肾脏和心脏病，寿命缩短了11-13年。严格的血糖控制可以减少 微血管并发症和不良心血管事件。胰岛素治疗对这类患者是必不可少的， 但也有缺点：a)只有1/3的患者达到了有针对性的血糖控制(HbA1c&lt；7%)；b)积极 胰岛素治疗增加了间歇性低血糖，这本身就缩短了生命；c)大多数T1糖尿病患者 胰岛素抵抗。有胰岛素抵抗的T1 DM患者的心血管风险是有胰岛素抵抗的患者的2.5倍 正常的胰岛素抵抗。我们建议测试一种新的方法来解决T1 DM的这些缺点 心理治疗。最近的临床试验已经测试了非胰岛素药与胰岛素联合治疗T1 DM，以改善 控制血糖，减少胰岛素需求。总体而言，这些试验显示糖化血红蛋白和胰岛素需求较低， 但有不可接受的副作用。理想的胰岛素辅助剂应该是：1)减少胰岛素需求和体重增加； 降低HbA1c；3)不需要频繁服用；4)有利于心脏功能。我们在老鼠身上的数据 表明UCn2基因转移在胰岛素抵抗小鼠中满足这些标准，我们最近 已发现UCn2基因转移可使血糖控制正常化，减少视网膜病变，改善心脏 在T1糖尿病小鼠模型中，该药物具有良好的抗糖尿病作用，并可降低死亡率。我们已经证明了静脉注射的效用。 编码具有旁分泌作用的转基因的载体，该旁分泌作用可增加胰岛素的敏感性和释放 糖尿病。这一策略使患者能够在办公室就诊期间通过一次注射载体进行治疗。它 将消除重复管理的需要，降低成本并提高合规性。最佳载体 为了实现这些目标，编码UCn2的8型腺相关病毒(AAV8)。这项提议的目标是 开发和优化这一方法，使其与胰岛素联合应用于T1 DM患者。 T1 DM是几种流行的改变生活和终生疾病的主要危险因素，这些疾病是 NHLBI：外周血管疾病、中风、心肌梗死和心力衰竭。这一发现和 开发更有效的治疗T1 DM的方法势在必行，这可能会降低糖尿病的患病率 与T1 DM相关的心血管并发症。当前提案的目标是测试这一新的 接近。

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 <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.