Phase 2 Study of rAAV1-CB-hAAT for Treatment of Alpha-1 Antitrypsin Deficiency

描述（由申请人提供）： α-1抗胰蛋白酶缺乏症是一种遗传性遗传疾病，其特征是血清α-1抗胰蛋白酶（AAT）水平降低，发生肺气肿和肝病的风险增加，在美国影响多达100，000人。目前唯一批准用于这种孤儿病的疗法是每周静脉输注从正常血浆供体纯化的AAT蛋白。目前的疗法供应不足，导致医生准确诊断绝大多数患者的积极性低，因为并非所有目前诊断的少数患者都能够接受治疗。本申请中提出的研究的长期目标是使用表达人AAT基因的重组腺相关病毒（rAAV）血清型1载体（rAAV 1-CB-hAAT）开发并推向市场用于治疗α-1抗胰蛋白酶缺乏症的新型基因治疗产品。rAAV载体独特地适用于体内基因治疗，因为它们是无毒的，在转导多种非分裂细胞类型方面是高效的，并且主要以附加体形式持续很长时间，导致转基因的长期表达。本研究计划的具体目的是进行rAAV 1-CB-hAAT的2期临床试验。 该研究是一项非随机、开放标签、多中心、序贯、三臂、2期临床试验，评估通过肌内（IM）注射施用rAAV 1-CB-hAAT载体的安全性和功效。每名参与者将接受rAAV 1-CB-hAAT一次。三组，每组三名受试者将通过IM注射以6 X 1011载体基因组（vg）/kg、1.9 X 1012 vg/kg或6 X 1012 vg/kg的剂量水平接受rAAV 1-CB-hAAT。组1中的受试者将接受分布在单个肌肉部位的总共10次IM注射，组2中的受试者将接受分布在3个肌肉部位的总共32次IM注射，组3中的受试者将接受分布在10个肌肉部位的100次IM注射。每次注射将以1.35 mL的体积以适当的载体浓度给予，以实现所需的总载体剂量，并且每个给药部位的注射密度（每4 cm 2皮肤表面积9次IM注射）将与先前使用rAAV 1-CB-hAAT的1期临床试验中耐受良好的注射密度相同。将通过评价不良事件、血液学和临床化学参数、肌肉活检的组织学检查和AAT血清抗体测量来监测安全性。疗效 将通过评价M特异性AAT和总AAT的血清浓度以及在等电聚焦凝胶上测定的血清AAT表型来测量。收集的其他信息将包括血液或精液中是否存在载体、血清抗AAV抗体滴度的变化以及T细胞对AAV和AAT应答的变化。这项2期试验的结果将用于开发一项3期研究，旨在满足该孤儿病基因治疗许可的要求。

DESCRIPTION (provided by applicant): Alpha-1 antitrypsin deficiency is an inherited, genetic condition characterized by reduced serum levels of alpha-1 antitrypsin (AAT) and increased risk of developing emphysema and liver disease, which affects up to 100,000 individuals in the United States. The only currently approved therapy for this orphan disease is weekly intravenous infusions of AAT protein that has been purified from normal plasma donors. The current therapy is in short supply, resulting in low physician motivation to accurately diagnose the vast majority of patients, since not all of the minority of patients who are currently diagnosed are able to receive treatment. The long-term objective of the research proposed in this application is to develop and bring to market a novel, gene therapy product for the treatment of alpha-1 antitrypsin deficiency, using a recombinant adeno-associated virus (rAAV) serotype 1 vector expressing the human AAT gene (rAAV1-CB-hAAT). rAAV vectors are uniquely suitable for in vivo gene therapy because they are non-toxic, highly efficient at transducing a wide variety of non-dividing cell types, and persist for long periods, primarily in episomal form, resulting in long-term expression of the transgene. The specific aim of this research proposal is to perform a Phase 2 clinical trial of rAAV1-CB-hAAT. The study is a non-randomized, open-label, multi-center, sequential, three-arm, Phase 2 clinical trial evaluating the safety and efficacy of administration of a rAAV1-CB-hAAT vector administered by intramuscular (IM) injection. Each participant will receive rAAV1-CB-hAAT on a single occasion. Three groups of three subjects each will receive rAAV1-CB-hAAT at dosage levels of 6 x 1011 vector genome (vg)/kg, 1.9 x 1012 vg/kg or 6 x 1012 vg/kg by IM injection. Subjects in group 1 will receive a total of 10 IM injections distributed across a single muscle site, subjects in group 2 will receive a total of 32 IM injections distributed across three muscle sites, and subjects in group 3 will receive 100 IM injections distributed across10 muscle sites. Each injection will be given in a volume of 1.35 mL, at the appropriate vector concentration to achieve the desired total vector dose, and the injection density at each administration site (nine IM injections per 4 cm2 skin surface area) will be the same as the injection density that was well tolerated in a previous Phase 1 clinical trial with rAAV1-CB-hAAT. Safety will be monitored by evaluation of adverse events, hematology and clinical chemistry parameters, histological examination of muscle biopsies, and measurement of serum antibodies to AAT. Efficacy will be measured by evaluation of serum concentrations of M-specific AAT and total AAT and serum AAT phenotype determined on isoelectric focusing gels. Additional information to be collected will include presence of the vector in blood or semen, changes in serum anti-AAV antibody titers, and changes in T cell responses to AAV and AAT. Results from this Phase 2 trial will be used to develop a Phase 3 study designed to satisfy the requirements for licensure of a gene therapy treatment for this orphan disease.