Adenylyl cyclase VIII gene therapy for CHF

腺苷酸环化酶 VIII 基因治疗 CHF

• 批准号: 6655318
• 负责人: H. Kirk Hammond
• 金额: $ 27.49万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6655318
• 关键词: adenylate cyclase; biotechnology; calcium transporting ATPase; clinical trial phase I; congestive heart failure; enzyme therapy; gene delivery system; gene therapy; heart contraction; heart function; human subject; human therapy evaluation; laboratory mouse; laboratory rat; patient oriented research; swine; transfection /expression vector; adenylate cyclase; biotechnology; calcium transporting ATPase; clinical trial phase I; congestive heart failure; enzyme therapy; gene delivery system; gene therapy; heart contraction; heart function; human subject; human therapy evaluation; laboratory mouse; laboratory rat; patient oriented research; swine; transfection /expression vector

Heart failure is the only cardiovascular disease that is increasing in prevalence and the outlook for a patient with dilated heart failure remains dismal despite recent advances in therapy. The key abnormality is the major focus of this Project. We have shown that the amount of adenylyl cyclase (AC) sets a limit on cAMP production. We then showed that over-expression of AC increases cardiac contractile function in transgenic mice. When AC is expressed in the setting of murine cardiomyopathy, cardiac function and survival are improved. Finally, we recently demonstrated that cardiac AC expression can be increased in a manner that can be applied clinically-through intracoronary delivery of an adenovirus encoding AC. The effects on LV function and cAMP generating capacity after intracoronary delivery are long-lasting and not associated with deleterious effects. These studies were conducted using AC type VI, a major isoform in mammalian heart. Cardiac-directed expression of ACVI or ACVIII, an isoform more typically found in brain than heart, shows similar favorable effects on cardiac contractility. But ACVIII exhibits unique properties. For example, compared to ACVI, ACVIII is less responsive to beta-adrenergic receptor (betaAR) stimulation, a potential advantage in the setting high catecholamine levels associated with congestive heart failure. We propose a gene therapy for heart failure. First, we will perform the necessary toxicology studies and bridging preclinical studies to support a Phase1/Phase 2 clinical trial of ACVIII gene therapy for severe heart failure (completed in the first funding year). We then will perform the clinical trial using intracoronary delivery of an adenovirus encoding human ACVIII for the treatment of dilated Class III/IV congestive heart failure (completed mid-way through Year 3). In the later phase of the award we will study other genes that might increase contractility and favorably influence symptoms and survival in heart failure. These studies will provide preclinical data sufficient to support a second IND filing so that the second Phase 1/Phase 2 clinical trial could be conducted in Year 4 and 5. A prime candidate is sarcoplasmic reticulum Ca2+ ATPase (SERCA2a). Hypotheses: 1. Intracoronary delivery of an adenovirus encoding ACVIII will improve heart function and reduce symptoms in patients with Class III/IV congestive heart failure. 2. Intracoronary delivery of an adenovirus encoding Ca2+ ATPase (SERCA2a) will improve heart function and reduce symptoms in patients with Class III/IV congestive heart failure.

心力衰竭是唯一增加患病率的心血管疾病，尽管治疗最近进展，但心力衰竭患者的外观仍然令人沮丧。关键异常是该项目的主要重点。我们已经表明，腺苷酸环化酶（AC）的量设定了营地生产的限制。然后，我们表明AC的过表达增加了转基因小鼠的心脏收缩功能。当AC在鼠心肌病的环境中表达时，心脏功能和存活率得到改善。最后，我们最近证明，可以以一种可以在腺病毒编码AC的腺病毒术后递送的方式增加心脏AC表达。冠状内输送后对LV功能和CAMP产生能力的影响是持久的，并且与有害效应无关。这些研究是使用哺乳动物心脏的主要同工型AC型进行的。 ACVI或ACVIII的心脏指导表达（一种比心脏更常见的同工型）对心脏收缩性显示出类似的有利作用。但是ACVIII具有独特的特性。例如，与ACVI相比，ACVIII对β-肾上腺素能受体（BETAAR）刺激的反应较低，这是与充血性心力衰竭相关的高儿茶酚胺水平的潜在优势。我们提出了一种用于心力衰竭的基因疗法。首先，我们将进行必要的毒理学研究和桥接临床前研究，以支持ACVIII基因疗法对严重心力衰竭的阶段/阶段2临床试验（在第一个资助年完成）。然后，我们将使用编码人ACVIII的腺病毒的冠状动脉内递送进行临床试验，以治疗扩张的III/IV类充血性心力衰竭（在第3年中期完成）。在奖项的后期，我们将研究其他可能增加收缩力并有利地影响心力衰竭症状和生存的基因。这些研究将提供足够的临床前数据以支持第二次IND归档，以便可以在第4年和5年进行第二阶段1/第2阶段的临床试验。主要候选者是肌浆网Ca2+ ATPase（SERCA2A）。假设：1。编码ACVIII的腺病毒的冠状动脉内分娩将改善心脏功能并减轻III/IV类充血性心力衰竭患者的症状。 2。编码Ca2+ ATPase（SERCA2A）的腺病毒的冠状动脉内递送将改善心脏功能并减轻III/IV类充血性心力衰竭患者的症状。