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

Urocortin-2 基因转移治疗 1 型糖尿病和相关左室功能障碍

• 批准号: 10649403
• 负责人: H. Kirk Hammond
• 金额: $ 79.26万
• 依托单位: RENOVA THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-20 至 2025-06-12
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10649403
• 关键词: Address; Adverse effects; Affect; Animal Model; Animals; Biodistribution; Blinded; Blood Glucose; Brain; Cardiovascular system; Clinical; Clinical Treatment; Clinical Trials; Corticotropin-Releasing Hormone; Data; Dependovirus; Development; Development Plans; Diabetes Mellitus; Disease; Effectiveness; Event; Fasting; Female; Frequencies; Functional disorder; Funding; Gastrointestinal tract structure; Gene Transduction Agent; Gene Transfer; Glucose tolerance test; Glycosylated hemoglobin A; Goals; Heart; Heart Diseases; Heart failure; Hyperglycemia; Hypoglycemia; Infusion procedures; Injections; Insulin; Insulin Resistance; Insulin deficiency; Insulin-Dependent Diabetes Mellitus; Intravenous; Investments; Kidney Diseases; Legal patent; Letters; Licensing; Life; Liver; Longevity; Macaca; Macaca mulatta; Measures; Metabolic; Methods; Microvascular Dysfunction; Modeling; Mus; Myocardial Infarction; Myocardial dysfunction; NOVA2 gene; National Heart, Lung, and Blood Institute; Office Visits; Patients; Peptides; Peripheral Vascular Diseases; Phase; Piper; Plasma; Pramlintide; Predisposition; Prevalence; Randomized; Rattus; Recommendation; Research Design; Retinal Diseases; Risk Factors; Safety; Saline; Satellite Viruses; Skeletal Muscle; Small Business Technology Transfer Research; Sprague-Dawley Rats; Streptozocin; Stroke; Structure; Technology; Testing; Toxicology; Transgenes; Weight Gain; blood glucose regulation; cardiovascular effects; cardiovascular risk factor; commercialization; cost; diabetes mellitus therapy; diabetic; effective therapy; efficacy testing; fasting glucose; glucose disposal; glycemic control; heart function; improved; insulin sensitivity; intravenous injection; male; mortality; mouse model; novel strategies; paracrine; pre-Investigational New Drug meeting; receptor; safety testing; sex; side effect; urocortin; vector

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.

摘要 1型糖尿病（T1 DM）在美国影响125万患者，每年有40，000名新患者。 寿命缩短11-13年，由于肾脏和心脏病。严格的血糖控制可降低 微血管并发症和不良心血管事件。胰岛素治疗对这些患者至关重要， 但有缺点：a）只有1/3的患者达到目标血糖控制（HbA 1c <7%）; B）积极的 胰岛素治疗增加了发作性低血糖，这本身缩短了寿命; c）大多数T1 DM患者发生 胰岛素抵抗伴胰岛素抵抗的T1 DM患者的心血管风险是伴胰岛素抵抗的T1 DM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 疗法最近的临床试验测试了非胰岛素药物与胰岛素联合治疗T1 DM，以改善 血糖控制和减少胰岛素需求。总的来说，这些试验显示HbA 1c和胰岛素需求较低， 但有不可接受的副作用一个理想的胰岛素辅助剂应该：1）减少胰岛素需求和体重增加; 2） 降低HbA 1c; 3）不需要频繁给药; 4）有利地影响心脏功能。我们在小鼠中的数据 表明尿皮质素2（UCn 2）基因转移在胰岛素抵抗小鼠中满足这些标准，我们最近 他们发现UCn 2基因转移可以使血糖控制正常化，减少视网膜病变，改善心脏功能， 功能，并降低T1 DM小鼠模型的死亡率。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，所述旁分泌作用增加胰岛素敏感性和胰岛素释放， 糖尿病该策略使患者能够在门诊期间通过单次注射载体进行治疗。它 将消除重复给药的必要性，降低成本并提高合规性。最佳矢量 实现这些目标的是编码UCn 2的腺相关病毒8型（AAV 8）。 开发并优化该方法，使其与胰岛素联合用于T1 DM患者。 T1 DM是几种常见的改变生命和终止生命的疾病的主要风险因素，这些疾病是 NHLBI：外周血管疾病、卒中、心肌梗死和心力衰竭。发现和 开发更有效的T1 DM治疗方法势在必行，并可能降低T1 DM的患病率。 与T1 DM相关的心血管并发症。目前提案的目标是测试这种新的 approach.