Adenylyl Cyclase Type VI for CHF

腺酰环化酶(AC)长期以来被认为是心肌细胞和其他组织中的关键效应分子 细胞。1998年，我们发现腺酰环化酶的数量限制了心肌细胞的能力。 来建立营地。随后的研究表明，AC基因的表达具有明显的有利作用 对正常和衰竭心脏的心血管功能的影响，包括整体左心室(LV)的增加 功能，提高存活率，防止有害的重塑。我们实验室的数据显示 AC的表达也与急性心肌梗死死亡率的降低有关。 我们建议进行一项经冠状动脉腔内注射编码腺酰环化酶类型的腺病毒的临床试验。 心力衰竭(CHF)患者的血管紧张素转换酶(VI，ACVI)。这些研究源于大量的临床前数据。 我们在当前计划的最初四年内获得的(现已提交续订)。我们 预计在当前计划的第5年内治疗患者，已完成除最终法规外的所有工作 里程碑。我们预计，第一次试验将在拟议方案的第三年完成。表演 与临床研究并行的载体开发和临床前研究将使 在五年任期内过渡到使用受调控表达载体进行第二阶段研究 拟议的续期奖。 I.B.假设。冠状动脉内注射编码ACVI的腺病毒将改善心脏 III/IV级充血性心力衰竭患者的功能及缓解症状 失败了。 具体目的1.确定经冠状动脉内给药的安全性和潜在疗效。 在1期/2期临床试验中，编码ACVI的腺病毒在III/IV级心力衰竭患者中的应用。 具体目的2.确定腺病毒冠状动脉内注射的安全性和有效性 III/IV级心脏患者的ACVI编码(具有调控表达) 二期临床试验失败。

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.