Gene Transfer for Galactosialidosis - Resub

半乳糖唾液酸贮积症的基因转移 - Resub

基本信息

批准号：
8627165
负责人：
ARTHUR W. NIENHUIS
金额：
$ 71.1万
依托单位：
ST. JUDE CHILDREN'S RESEARCH HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8627165
关键词：
A Mouse Adolescence Adolescent and Young Adult Advanced Development Age Animals Apolipoproteins Biochemical Biodistribution Capsid Proteins Carboxypeptidase Case Study Child Support Childhood Clinical Clinical Trials Clinical assessments Code Comparative Study Data Defect Demography Development Disease Dose Enhancers Enrollment Factor IX Galactosidase Gene Transfer Genes Genomics Goals Hemophilia B Hepatic Human Image Individual Informed Consent Injection of therapeutic agent Intravenous infusion procedures Laboratories Liver Lysosomal Storage Diseases Mediating Methodology Modeling Monitor Mus Neuraminidase Neurologic Participant Patients Phase I/II Trial Phenotype Pilot Projects Production Protein C Inhibitor Proteins Protocols documentation Recombinants Recruitment Activity Reporting Resolution Risk Running Serotyping Subgroup Terminal Repeat Sequences Testing Time Toxic effect Treatment Efficacy Viral Work adeno-associated viral vector base carboxypeptidase C clinical lot clinically relevant demographics design disease phenotype experience gene therapy infancy meetings mouse model nonhuman primate novel patient population pre-clinical preclinical evaluation preclinical study promoter public health relevance response safety testing success therapeutic protein vector vector genome

项目摘要

DESCRIPTION (provided by applicant): This project is focused on the development of gene therapy for galactosialidosis (GS), an autosomal recessive lysosomal storage disease belonging to the glycoproteinosis subgroup. GS is caused by a primary defect in the lysosomal carboxypeptidase, protective protein/cathepsin A, that results in the secondary combined deficiency of ¿- galactosidase and neuraminidase. The initial participants targeted for gene transfer will be individuals with the late, infantile phenotype in that survival into childhood and adolescence is common without accompanying neurological signs allowing reversal of the somatic phenotype to be of high potential clinical relevance. We have made the following advances which support the application of gene transfer into the liver for the treatment of GS: 1) developed a novel, rAAV self-complementary vector encoding -/- PPCA and shown that it can correct phenotype in the GS (PPCA ) mouse model; 2) demonstrated that an analogous rAAV vector encoding human coagulation Factor IX restores FIX production in participants in a clinical trial with hemophilia B; 3) implemented a GMP compliant production and purification methodology for the hPPCA vector that we anticipate using in our clinical trial; and 4) defined with the FDA the remaining pre-clinical studies necessary to obtain an IND for a gene transfer trial for GS. In Specific Aim 1, we propose to produce a clinical lot of our self-complementary, rAAV hPPCA vector and in Specific Aim 2 to perform the final pre-clinical dose finding, biodistribution and toxicity studies in the PPCA mouse model. In Sub-Aim 3.1, we have begun to identify and characterize the clinical features and demography of patients with galactosialidosis with a goal of identifying a subgroup with the late infantile form for a gene transfer trial. Sub-am 3.2 is to perform the proposed gene transfer trial for participants with galactosialidosis. The tril will be monitored for evidence of gene transfer, for biochemical evidence of PPCA production and for correction of the clinical manifestations of the disorder.

描述（由应用提供）：该项目的重点是开发半乳糖症基因疗法（GS），这是一种属于糖蛋白酶亚组的常染色体隐性溶酶体储存疾病。 GS是由溶酶体羧肽酶（受保护的蛋白/组织蛋白酶A）的主要缺陷引起的，这导致了二次组合缺陷 - 半乳糖苷酶和神经瘤酶。针对基因转移的最初参与者将是患有该生存期间晚期，婴儿表型的个体，青少年很常见，没有参与神经系统迹象，从而使体型表型的逆转具有很高的潜在临床相关性。我们已经取得了以下进展，支持基因转移到肝脏的治疗中的应用：1）开发了一种新颖的RAAV自我平均矢量编码 - / - PPCA，并表明它可以纠正GS（PPCA）小鼠模型中的表型； 2）证明了编码人类凝血因子IX的类似RAAV载体修复了与血友病B的临床试验中的参与者中的生产； 3）为HPPCA矢量实施了符合GMP的生产和纯化方法，我们预计在我们的临床试验中使用该方法； 4）用FDA定义了其余的临床前研究，以获取GS基因转移试验的IND。在特定的目标1中，我们建议在PPCA小鼠模型中生产我们的自我平衡量，RAAV HPPCA矢量和特定目标2中的临床量，以执行最终的临床前剂量发现，生物分布和毒性研究。在Sub-aim 3.1中，我们开始识别和表征半乳突病患者的临床特征和人口统计学，目的是确定具有晚期基础设施形式的亚组，以进行基因转移试验。 SUB-AM 3.2是为半乳糖菌病参与者进行拟议的基因转移试验。将监视该三物体的基因转移证据，生化生产的生化证据以及校正该疾病的临床表现。