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

AAVrh.10hFXN 疗法治疗弗里德赖希共济失调心肌病的 IA/IB 期研究

• 批准号: 10274784
• 负责人: RONALD G CRYSTAL
• 金额: $ 239.97万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10274784
• 关键词: Adverse event; Affect; Arrhythmia; Ataxia; Automobile Driving; Biological Markers; Capsid; Cardiac; Cardiomyopathies; Cessation of life; Clinical; Clinical Research; Clinical Trials; Code; Complementary DNA; DNA cassette; Data; Dependovirus; Development; Disease; Dose; Echocardiography; Electrocardiogram; Enrollment; Experimental Animal Model; Fibrosis; Friedreich Ataxia; Gene Expression; Genes; Genetic; Genome; Goals; Heart; Heart failure; Hereditary Disease; Human; Hypertrophy; Individual; Inherited; Institutional Review Boards; Intravenous; Introns; Investigational Drugs; Left; Left Ventricular Dysfunction; Left Ventricular Hypertrophy; Left Ventricular Remodeling; Life; Link; Mediating; Mitochondria; Monitor; Morbidity - disease rate; Myocardial; Myocardial tissue; Outcome; Outpatients; Parents; Patients; Phase; Phase Ia/Ib Clinical Trial; Phenotype; Procedures; Production; Protocols documentation; Quality Control; Records; Reporting; Risk; Route; Safety; Secondary to; Serotyping; Serum; Statistical Data Interpretation; Therapeutic; Time; Toxicology; Variant; Ventricular; base; cardiac magnetic resonance imaging; coronary fibrosis; efficacy clinical trial; efficacy study; frataxin; gene transfer vector; human study; improved; inherited cardiomyopathy; intravenous administration; manufacturing process; mouse model; nervous system disorder; nonhuman primate; open label; preclinical efficacy; preservation; promoter; safety assessment; therapeutic gene; vector

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.

抽象的。该R61/R33提案的目的是进行IA/IB期临床研究 aavrh.10Hfxn（一种与人frataxin编码的腺相关病毒的血清型RH.10）用于治疗 弗里德里希共济失调（FA）的心脏表现，最常见的共济失调。 FA是致命的， 目前，不可治疗的疾病。大多数情况是由Frataxin（FXN）基因中的内含子变体引起的。什么时候 从父母双方继承下来，FXN基因表达的单倍不足。尽管 进行性神经系统疾病限制了迁移率，心肌病负责大量发病率和 继发性心力衰竭和心律不齐的60％的死亡。来自我们的心脏MRI（CMR）数据 小组和其他人表明，与FA相关的心肌病最初表现出左增加 心肌前心肌肿块（一种可能可逆的表型）在心肌发展之前 纤维化（不可逆损害）。 aavrh.10hfxn，用于用于该的治疗基因转移载体 拟议的人类研究是一种非人类灵长类动物的血清型RH.10带有本构启动子 驱动正常的人frataxin cDNA。 aavrh.10hfxn将静脉注射，矢量和 在实验动物模型中有效地为心脏传递基因的路线。基于我们的临床前 静脉内AAVRH.10HFXN的两个鼠模型中的效率数据逆转了FA的后果 心肌病，加上大量的安全数据，我们准备启动IA/IB期临床试验 以以下目标。 R61 AIM 1。准备并提交调查新药包并获得 FDA和其他监管团体（机构审查委员会，生物安全委员会）的批准启动 IA/IB期临床试验。里程碑。全面批准启动临床试验的A和B部分， 在A部分AIM 2和Milestone中注册第一个主题。制造临床级AAVRH.10HFXN A部分（安全/剂量范围）临床试验。 R33 AIM 3。进行A部分（安全/剂量范围）试验 确定AAVRH的最大耐受剂量。10HFXN治疗FA的心脏表现。 里程碑。启动和完整评估n = 9个人（每剂3剂，3剂），并有一个经过审核的最终 报告。 R33 AIM 4和里程碑。 B部分制造临床级AAVRH.10HFXN（安全/初步 有效性）临床试验。 R33 AIM 5。以最高 A. Milestone的耐受剂量。 n = 15个人的完整评估，并有经过审核的最终 报告。鉴于遗传差异负责多种形式的心肌病，而现有 治疗有限，这项研究提供了潜在的治疗范式转变，以反向心脏表型 从而改善了广泛的遗传介导患者的临床结果 心肌病风险不利的LV重塑及其毁灭性的临床后果。