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.

抽象的 1型糖尿病（T1DM）每年有40,000名新患者在美国影响125万患者。 由于肾脏和心脏病，寿命缩短了11 - 13年。紧密的葡萄糖控制减少 微血管并发症和不良心血管事件。胰岛素治疗对于此类患者至关重要 但存在缺点：a）只有3分之一的患者获得靶向葡萄糖对照（HBA1C <7％）； b）侵略性 胰岛素疗法增加了发作性低血糖，这本身会缩短寿命。 c）大多数T1DM患者发展 胰岛素抵抗。 T1DM胰岛素抵抗患者的心血管风险高2.5倍，而患有 正常的胰岛素抵抗。我们建议测试一种解决T1DM中这些缺点的新方法 治疗。最近的临床试验已经测试了非胰岛素与T1DM中胰岛素联合使用的非胰岛素剂，以改善 血糖控制并减少胰岛素要求。通常，这些试验显示HBA1C和胰岛素需求较低， 但是不可接受的副作用。胰岛素的理想辅助方法：1）减少胰岛素需求和体重增加； 2） 减少HBA1C； 3）需要不经常给药； 4）有利影响心脏功能。我们在小鼠中的数据 表明尿科素2（UCN2）基因转移符合胰岛素耐药小鼠中的这些标准，我们最近 已经发现UCN2基因转移使血糖控制归一化，减少视网膜病，改善心脏 功能，并降低T1DM鼠模型中的死亡率。我们已经显示了静脉输送的效用 用旁分泌作用编码转基因的向量，从而提高了胰岛素敏感性并释放 糖尿病。该策略使患者在办公室访问期间可以通过单次注射矢量进行治疗。它 将消除重复管理的需求，降低成本并提高合规性。最好的矢量 为了实现这些目标，是腺相关的8型病毒（AAV8），编码UCN2。该提案的目标是 为了开发并最佳地完善这种方法，可与T1DM患者同时使用胰岛素。 T1DM是几种普遍改变生活和生命终止疾病的主要危险因素，这是 NHLBI：周围血管疾病，中风，心肌梗塞和心力衰竭。发现和 开发更有效的T1DM疗法是必须的，并且可能会降低 与T1DM相关的心血管并发症。当前建议的目的是测试这个新的 方法。