New Approaches to Gene Therapy for Alpha-1 Antitrypsin Deficiency

治疗 Alpha-1 抗胰蛋白酶缺乏症的基因治疗新方法

• 批准号: 9071187
• 负责人: Terence R. Flotte
• 金额: $ 225.28万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9071187
• 关键词: Address; Affect; Biotechnology; CRISPR/Cas technology; Capsid; Chronic Obstructive Airway Disease; Clinical Trials; Clustered Regularly Interspaced Short Palindromic Repeats; DNA cassette; Disease; Doctor of Medicine; Funding; Generations; Genes; Goals; Immunologics; Inherited; Injection of therapeutic agent; Institutes; Intramuscular Injections; Isolated limb perfusion; Knockout Mice; Laboratories; Liver; Liver diseases; Lung diseases; Mediating; Mendelian disorder; MicroRNAs; Molecular; Mus; Muscle; Mutation; National Heart, Lung, and Blood Institute; Patients; Phase; Phase I Clinical Trials; Phenotype; Physicians; Pulmonary Emphysema; RNA; Recombinant adeno-associated virus (rAAV); Regulatory T-Lymphocyte; Research; Research Personnel; Resistance; Respiratory physiology; Role; Serum; System; Techniques; Therapeutic; Time; Transgenic Animals; Translations; Work; alpha 1-Antitrypsin; alpha 1-Antitrypsin Deficiency; base; experience; gene therapy; in vivo; innovation; knock-down; mutant; next generation; novel; novel strategies; pre-clinical; programs; public-private partnership; safety study; therapy design; translational study; vector

 DESCRIPTION (provided by applicant): The overall goal of this translational program is to develop a definitive molecular therapy for lung disease due to alpha-1 antitrypsin (AAT) deficiency, a relatively common single gene disease due to mutations in the AAT gene. The program builds on the experience of investigators in developing several different versions of recombinant adeno-associated virus (rAAV)-based gene therapies for AAT deficiency since the late 1990's. Previous NHLBI-funded work by the program director's laboratory included proof-of-concept (POC) studies, formal IND-enabling safety studies, and a phase 1 trial of intramuscular injection of a 1st generation rAAV2- AAT (on a physician IND). Subsequently, the same gene cassette was packaged in rAAV1-AAT for IM injection (2nd generation rAAV1-AAT) was likewise studied through POC, IND-enabling and phase 1 and phase 2a studies in a public-private partnership between NHLBI funding and funding by a small biotechnology company (AGTC). These studies showed serum AAT expression persisting for several years at level only 30-fold below the therapeutic threshold and demonstrated an important role for the induction of regulatory T cells (Tregs) in these patients. In the coming proposal, a group of investigators within the UMMS Horae Gene Therapy Center (GTC) and the RNA Therapeutics Institute (RTI) have come together to push translational studies of rAAV-AAT of the 2nd generation vector along with a number of newer approaches. These newer approaches include innovative RNA-based therapeutics, such as synthetic miRNAs (3rd generation), CRISPR/Cas9 approaches (4th generation), and novel AAV capsids (Nth generation). Additional innovation and accelerated translation is provided by superb research cores, including a transgenic animal core that has used the CRISPR/Cas9 system to create an AAT null mouse, respiratory physiology core to define the emphysema phenotype in these mice, and a vector core that will both innovate and provide high quality vector for all projects. With these successive generations of vectors, this program seeks to address the unmet need for gene therapy for lung disease due to alpha-1 antitrypsin (AAT) deficiency with an important focus on "liver-sparing" systemic gene therapy, designed to treat AAT lung disease without exacerbating AAT liver disease. Narrative: This proposal seeks to use the most cutting edge scientific techniques in gene therapy to develop a way to treat an inherited lung disease, called AAT deficiency. This disease leads to a form chronic obstructive pulmonary disease (COPD) and emphysema, which overall affect over 11 million patients in the US. AAT deficiency is less common than non-inherited forms of COPD, with estimates ranging from approximately 10,000 to 100,000 cases in the US, with many cases going undiagnosed. PROJECT 1: Clinical Trial and Immunologic aspects of muscle-directed rAAV1-AAT gene Therapy (Flotte, Terence R., M.D.)

 描述（由申请人提供）：该转化计划的总体目标是开发一种针对 α-1 抗胰蛋白酶（AAT）缺乏症引起的肺部疾病的明确分子疗法，这是一种由于 AAT 基因程序突变而导致的相对常见的单基因疾病。自 1990 年代后期以来，研究人员开发了几种不同版本的基于重组腺相关病毒 (rAAV) 的基因疗法来治疗 AAT 缺陷。项目主任实验室包括概念验证 (POC) 研究、正式的 IND 安全性研究以及肌肉注射第一代 rAAV2-AAT 的 1 期试验（在医生 IND 上）。包装在用于肌内注射的 rAAV1-AAT 中（第二代 rAAV1-AAT）同样通过 POC、IND 启用以及 1 期和 2a 期研究进行了研究NHLBI 资助和一家小型生物技术公司 (AGTC) 资助的公私合作伙伴关系中的这些研究表明，血清 AAT 表达水平持续数年，仅低于治疗阈值 30 倍，并证明了其对于诱导监管的重要作用。在即将到来的提案中，UMMS Horae 基因治疗中心 (GTC) 和 RNA 治疗研究所 (RTI) 的一组研究人员齐心协力推动 T 细胞的转化研究。第二代载体的 rAAV-AAT 以及许多更新的方法包括基于 RNA 的创新疗法，例如合成 miRNA（第三代）、CRISPR/Cas9 方法（第四代）和新型 AAV 衣壳（第 N 代）。卓越的研究核心提供了额外的创新和加速转化，包括使用 CRISPR/Cas9 系统创建 AAT 无效小鼠的转基因动物核心、定义 AAT 的呼吸生理学核心。这些小鼠的肺气肿表型，以及将为所有项目提供创新和高质量载体的载体核心，通过这些连续几代的载体，该项目旨在解决由于 α-1 抗胰蛋白酶引起的肺部疾病基因治疗的未满足需求。 (AAT) 缺乏症，重点关注“保肝”全身基因治疗，旨在治疗 AAT 肺病而不加剧 AAT 肝病。 叙述：该提案旨在利用基因治疗中最尖端的科学技术来开发一种治疗遗传性肺病（称为 AAT 缺乏症）的方法。这种疾病会导致慢性阻塞性肺病 (COPD) 和肺气肿，从而总体影响。在美国，AAT 缺乏症比非遗传性慢性阻塞性肺病 (COPD) 少见，估计美国有大约 10,000 至 100,000 例患者，其中许多病例正在接受治疗。未确诊。 项目 1：肌肉定向 rAAV1-AAT 基因的临床试验和免疫学方面 治疗（Flotte，Terence R.，医学博士）