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

基本信息

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
项目类别：
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

项目摘要

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.

摘要：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）用于治疗弗里德赖希共济失调 (FA) 的心脏表现，最常见的遗传性共济失调是致命的。目前，大多数病例是由 frataxin (FXN) 基因的内含子变异引起的；从父母双方遗传，导致 FXN 基因表达单倍体不足。进行性神经系统疾病限制了活动能力，心肌病是导致大量发病率和根据我们的心脏 MRI (CMR) 数据，60% 的死亡继发于进行性心力衰竭和心律失常。小组和其他人证明 FA 相关心肌病最初表现为左心室增加心肌发育之前的心室 (LV) 心肌质量（潜在可逆表型）纤维化（不可逆损伤），AAVrh.10hFXN，用于治疗的基因转移载体。拟议的人类研究，是一种非人灵长类衍生的血清型 rh.10 衣壳，具有组成型启动子驱动正常人frataxin cDNA的载体将被静脉内施用。根据我们的临床前研究，在实验动物模型中有效地将基因传递到心脏的途径。两种小鼠模型的疗效数据，其中静脉注射 AAVrh.10hFXN 可逆转 FA 的后果心肌病，加上广泛的安全性数据，我们准备启动 IA/IB 期临床试验 R61 目标 1. 准备并提交研究性新药包并获得收益。 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 期临床试验获得监管机构的全面批准，启动临床试验的 A 部分和 B 部分，在 A 部分中注册第一个科目。 R61 目标 2 和里程碑制造临床级 AAVrh.10hFXN。 A 部分（安全性/剂量范围）临床试验 R33 目标 3. 进行 A 部分（安全性/剂量范围）试验确定 AAVrh.10hFXN 治疗 FA 心脏表现的最大耐受剂量。里程碑：启动并完成对 n=9 人的评估（3 剂，每剂 3 剂），并进行最终审核。报告。R33 目标 4 和里程碑 B 部分的生产临床级 AAVrh.10hFXN。 R33目标5.最高进行B部分安全性/初步疗效研究。 A 部分的耐受剂量。里程碑对 n=15 个人进行完整评估，并进行最终审核。报告指出，遗传变异是造成多种形式的心肌病的原因，并且现有的心肌病也是如此。治疗方法有限，这项研究为逆转心脏表型提供了潜在的治疗范式转变从而改善广泛的遗传介导患者的临床结果心肌病存在不良左心室重塑及其破坏性临床后果的风险。