Phase IA/IB Study of AAVrh.10hFXN Therapy to Treat the Cardiomyopathy of Friedreich's Ataxia

抽象的。该R61/R33提案的目标是开展IA/IB期临床研究 AAVRh.10hFXN(编码人Frataxin的血清型Rh.10腺相关病毒)治疗 弗里德里希共济失调(FA)的心脏表现，最常见的遗传性共济失调。FA是致命的， 目前，无法治愈的疾病。大多数病例是由Frataxin(FXN)基因内含子变异引起的；当 遗传自双亲，导致FXN基因表达单倍性不足。而当 进行性神经系统疾病限制了行动能力，心肌病是导致大量发病率和 60%的死亡继发于进行性心力衰竭和心律失常。心脏磁共振(CMR)数据来自我们的 研究小组和其他人证明，FA相关的心肌病最初表现为左侧增加 发生心肌梗死前的室性(LV)心肌质量(一种潜在的可逆表型) 纤维化(不可逆转的损害)。治疗性基因转移载体AAVRH.10hFXN 拟议的人类研究，是一种非人类灵长类衍生的血清型r.10衣壳蛋白，具有构成启动子。 驱动正常的人类Frataxin基因。AAVRh.10hFXN将静脉注射，载体和 在实验动物模型中有效地将基因输送到心脏的途径。基于我们的临床前研究 静脉注射AAVRh.10hFXN逆转FA后果的两种小鼠模型的疗效数据 心肌病，加上广泛的安全性数据，我们准备启动IA/IB期临床试验 目标有以下几点。R61目标1.准备和提交研究用新药包装并获得 FDA和其他监管组织(机构审查委员会，生物安全)批准启动一项 IA/IB期临床试验。这是一个里程碑。监管部门完全批准启动临床试验的A部分和B部分， 在A部分注册第一个科目。R61目标2和里程碑。临床级AAVRH.10hFXN的研制 A部分(安全性/剂量范围)临床试验。R33目标3.开展A部分(安全/剂量范围)试验以 确定AAVRh.10hFXN治疗FA心脏表现的最大耐受量。 这是一个里程碑。启动并完成对n=9人的评估(3剂，每剂3剂)，并有经审计的最终结果 报告情况。R33目标4和里程碑。B部分临床AAVRh.10hFXN的制造(安全/初步 疗效)临床试验。R33目标5.最高限度地开展B部分安全性/初步疗效研究 A部分里程碑的可耐受剂量。完成对n=15个人的评估，并提供经审计的最终报告 报告情况。鉴于遗传变异是多种形式的心肌病的原因，而现有的 治疗是有限的，这项研究提供了一种潜在的治疗范式转变来逆转心脏表型 从而改善广泛的遗传介导型糖尿病患者的临床结果 高危心肌病、不良的左室重构及其破坏性的临床后果。

Abstract. The goal of this R61/R33 proposal is to carry out a phase IA/IB clinical study of AAVrh.10hFXN (a serotype rh.10 adeno-associated virus coding for human frataxin) to treat cardiac manifestations of Friedreich’s ataxia (FA), the most common inherited ataxia. FA is a fatal, presently, untreatable disorder. Most cases result from intron variants in the frataxin (FXN) gene; when inherited from both parents, there is resulting haploinsufficiency of FXN gene expression. While progressive neurologic disease limits mobility, cardiomyopathy is responsible for substantial morbidity and 60% of deaths secondary to progressive heart failure and arrhythmias. Cardiac MRI (CMR) data from our group and others demonstrate that FA-associated cardiomyopathy initially manifests with increased left ventricular (LV) myocardial mass (a potentially reversible phenotype) prior to development of myocardial fibrosis (irreversible damage). AAVrh.10hFXN, the therapeutic gene transfer vector to be used in the proposed human study, is a nonhuman primate-derived serotype rh.10 capsid with a constitutive promoter driving the normal human frataxin cDNA. AAVrh.10hFXN will be administered intravenously, a vector and route which in experimental animal models effectively delivers genes to the heart. Based on our preclinical efficacy data in two murine models in which intravenous AAVrh.10hFXN reverses the consequences of FA cardiomyopathy, together with extensive safety data, we are ready to initiate a phase IA/IB clinical trial with the following aims. R61 aim 1. Prepare and submit an Investigational New Drug package and gain approval from the FDA and other regulatory groups (Institutional Review Board, Biosafety) to initiate a phase IA/IB clinical trial. Milestone. Full regulatory approval to initiate parts A and B of the clinical trial, enroll the 1st subject in part A. R61 aim 2 and milestone. Manufacture clinical grade AAVrh.10hFXN for the part A (safety/dose-ranging) clinical trial. R33 aim 3. Carry out the part A (safety/dose-ranging) trial to determine the maximum tolerable dose of AAVrh.10hFXN therapy for the cardiac manifestations of FA. Milestone. Initiate and complete assessment of n=9 individuals (3 doses, 3 each), with an audited final report. R33 aim 4 and milestone. Manufacture clinical grade AAVrh.10hFXN for part B (safety/preliminary efficacy) clinical trial. R33 aim 5. Carry out the part B safety/preliminary efficacy study at the highest tolerable dose from part A. Milestone. Complete assessment of n=15 individuals, with an audited final report. Given that genetic variance is responsible for many forms of cardiomyopathy and that existing treatments are limited, this study offers a potential therapeutic paradigm shift to reverse cardiac phenotype and thus improve clinical outcomes for a broad range of patients with genetically mediated cardiomyopathies at risk adverse LV remodeling and its devastating clinical consequences.