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性疾病，其特征是血清α-1抗胰蛋白酶(AAT)水平降低，患肺气肿和肝病的风险增加，在美国有多达10万人受到影响。目前唯一被批准的治疗这种孤儿疾病的方法是每周静脉输注从正常血浆捐献者那里提纯的AAT蛋白。目前的治疗方法供不应求，导致医生缺乏对绝大多数患者进行准确诊断的动力，因为并不是所有目前确诊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利用表达人AAT基因的重组腺相关病毒(RAAV)血清1型载体(rAAV1-CB-HAAT)开发并将一种用于治疗α-1抗胰蛋白酶缺乏症的新型基因治疗产品推向市场。RAAV载体是唯一适合于体内基因治疗的载体，因为它们无毒，高效地转导各种类型的未分裂细胞，并且持续时间长，主要是以表型形式存在，导致转基因的长期表达。这项研究计划的具体目的是进行rAAV1-CB-HAAT的第二阶段临床试验。 这项研究是一项非随机、开放标签、多中心、序贯、三臂、2期临床试验，评估肌肉注射rAAV1-CB-HAAT载体的安全性和有效性。每位参与者将一次性获得rAAV1-CB-HAAT。按6×1011载体基因组(VG)/kg、1.9×1012 Vg/kg或6×1012 Vg/kg的剂量水平肌注rAAV1-CB-Haat，每组3人。第1组受试者将接受分布在单个肌肉部位的总共10次IM注射，第2组受试者将接受总共32次分布在3个肌肉部位的IM注射，而第3组受试者将接受分布在10个肌肉部位的100次IM注射。每次注射的体积为1.35毫升，具有适当的载体浓度，以达到所需的总载体剂量，并且每个给药部位的注射密度(每4cm2皮肤表面积9次IM注射)将与先前使用rAAV1-CB-HAAT进行的1期临床试验中耐受性良好的注射密度相同。安全性将通过评估不良事件、血液学和临床化学参数、肌肉活检的组织学检查和血清AAT抗体的测定来监测。功效 将通过评估血清M特异性AAT和总AAT的浓度以及等电聚焦凝胶测定的血清AAT表型来进行测量。将收集的其他信息将包括血液或精液中存在载体，血清抗AAV抗体效价的变化，以及T细胞对AAV和AAT的反应的变化。这项第二阶段试验的结果将用于开发一项第三阶段研究，旨在满足这种孤儿疾病的基因治疗获得许可的要求。

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.