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

抽象的。本R61/R33提案的目标是开展IA/IB期临床研究， AAVrh.10hFXN（编码人共济失调蛋白的血清型rh.10腺相关病毒）用于治疗 Friedreich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共济失调蛋白（FXN）基因的内含子变异引起的; 从双亲遗传，导致FXN基因表达的单倍不足。而 进行性神经系统疾病限制了活动性，心肌病是导致大量发病的原因， 60%的死亡继发于进行性心力衰竭和心律失常。心脏MRI（CMR）数据来自我们的 研究组和其他研究表明，FA相关心肌病最初表现为左心室肥厚， 心室（LV）心肌质量（一种潜在可逆表型），发生心肌梗死前 纤维化（不可逆损伤）。AAVrh.10hFXN，用于治疗性基因转移载体， 提出的人类研究，是一种非人灵长类动物来源的血清型rh.10衣壳，具有组成型启动子 驱动正常人共济失调蛋白cDNA。将静脉内施用AAVrh.10hFXN，载体和 在实验动物模型中，该途径有效地将基因传递到心脏。基于我们的临床前 在两种小鼠模型中的功效数据，其中静脉内AAVrh.10hFXN逆转FA的结果 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 具有以下目的。R61 aim 1.准备并提交研究性新药包， FDA和其他监管机构（机构审查委员会，生物安全）批准启动 IA/IB期临床试验。里程碑全面监管批准启动临床试验的A部分和B部分， 入组A部分的第1例受试者。R61目标2和里程碑。生产临床级AAVrh.10hFXN，用于 A部分（安全性/剂量范围）临床试验。R33瞄准3.开展A部分（安全性/剂量范围）试验， 确定用于FA的心脏表现的AAVrh.10hFXN疗法的最大耐受剂量。 里程碑启动并完成对n=9名受试者的评估（3次给药，每次3次），并提供稽查的最终结果 次报告. R33目标4和里程碑。生产临床级AAVrh.10hFXN用于部分B（安全性/初步 疗效）临床试验。R33瞄准5.以最高水平开展B部分安全性/初步有效性研究 A部分的耐受剂量。里程碑完成对n=15人的评估，并提供经审计的最终结果 次报告.鉴于遗传变异是导致多种形式心肌病的原因， 治疗是有限的，这项研究提供了一个潜在的治疗范式转变，以扭转心脏表型 从而改善了广泛的遗传介导的 心肌病的风险，不利的左心室重塑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.