Adenylyl Cyclase Type VI for CHF

CHF 腺苷酸环化酶 VI 型

• 批准号: 7217648
• 负责人: H. Kirk Hammond
• 金额: $ 70.79万
• 依托单位: VETERANS MEDICAL RESEARCH FDN/SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7217648
• 关键词: Adenoviridae; adenylate cyclase; angiography; biotechnology; cardiac myocytes; cardiovascular disorder chemotherapy; clinical trial phase I; clinical trial phase II; congestive heart failure; drug screening /evaluation; echocardiography; electrocardiography; gene delivery system; gene expression; heart function; human subject; human therapy evaluation; patient oriented research; sign /symptom; transfection /expression vector

Adenylyl cyclase (AC) has long been recognized as a pivotal effector molecule in cardiac myocytes and other cells. In 1998 we showed that the amount of adenylyl cyclase sets a limit on the ability of cardiac myocytes to generate cAMP. Subsequent studies showed that AC gene expression has a pronounced favorable effect on cardiovascular function in normal and failing hearts, including increased global left ventricular (LV) function, increased survival and prevention of deleterious remodeling. Data from our laboratory indicate that AC expression also is associated with reduced mortality in acute myocardial infarction. We propose a clinical trial of intracoronary delivery of an adenovirus encoding adenylyl cyclase type VI (ACVI) in patients with congestive heart failure (CHF). These studies stem from extensive preclinical data that we have obtained during the initial four years of the current Program (now submitted for renewal). We expect to be treating patients in Year 5 of the current Program, having achieved all but the final regulatory milestones. We project that this first trial will be complete in Year 3 of the proposed Program. Performing vector development and preclinical studies in parallel with the clinical study will enable a seamless transition to the conduct of a Phase 2 study using a regulated expression vector during the five year tenure of the proposed renewal award. I.B. Hypothesis. Intracoronary delivery of an adenovirus encoding ACVI will improve heart function and reduce symptoms in patients with Class III/IV congestive heart failure. Specific Aim 1. To determine the safety and potential efficacy of intracoronary delivery of an adenovirus encoding ACVI in patients with Class III/IV heart failure in a Phase 1/Phase 2 clinical trial. Specific Aim 2. To determine the safety and efficacy of intracoronary delivery of an adenovirus encoding ACVI (with regulated expression) in patients with Class III/IV heart failure in a Phase 2 clinical trial.

长期以来，在心肌细胞和其他中，腺苷酸环化酶（AC）长期以来被认为是枢轴效应分子 细胞。在1998年，我们表明腺苷酸环化酶的量设定了心肌细胞的能力 产生营地。随后的研究表明，AC基因表达具有明显的有利作用 关于正常和失败心脏的心血管功能，包括增加全局左心室（LV） 功能，增加生存和预防有害重塑。我们实验室的数据表明 该AC表达也与急性心肌梗塞的死亡率降低有关。 我们提出了一项编码腺苷酸环化酶类型的腺病毒内递送的临床试验 充血性心力衰竭（CHF）患者的VI（ACVI）。这些研究源于广泛的临床前数据 我们在当前计划的最初四年（现已提交续订）中获得的。我们 希望在当前计划的第五年度治疗患者，除了最终的监管外，所有人都将 里程碑。我们预测，第一个试验将在拟议计划的第三年完成。表演 与临床研究并行的媒介发展和临床前研究将使无缝 在五年任期内使用受调节表达载体的2期研究过渡到2期研究 拟议的更新奖。 I.B.假设。编码ACVI的腺病毒的冠状动脉递送将改善心脏 III/IV类充血性心脏患者的功能并减少症状 失败。 具体目的1。确定冠状内递送的安全性和潜在功效 在第1阶段/第2期临床试验中，腺病毒编码III/IV类心力衰竭的患者的ACVI。 具体目的2。确定腺病毒冠状动脉内递送的安全性和功效 在III/IV类心脏的患者中编码ACVI（具有调节表达） 在第二阶段临床试验中失败。