Gene Transfer for Galactosialidosis - Resub

描述（由申请人提供）：该项目的重点是开发半乳糖唾液酸沉积症（GS）的基因治疗，GS是一种属于糖蛋白沉积症亚组的常染色体隐性溶酶体贮积病。GS是由溶酶体羧肽酶、保护蛋白/组织蛋白酶A的原发性缺陷引起的，其导致半乳糖苷酶和神经氨酸酶的继发性联合缺陷。基因转移的最初目标参与者将是具有晚期婴儿表型的个体，其存活到儿童期， 青春期是常见的，没有伴随的神经系统体征，使得体细胞表型的逆转具有高度潜在的临床相关性。我们已经取得了以下进展，支持应用基因转移到肝脏中治疗GS：1）开发了一种新的rAAV自身互补载体编码-/- PPCA，并显示它可以在GS（PPCA）小鼠模型中校正表型;（二）证明了编码人凝血因子IX的类似rAAV载体在患有血友病B的临床试验的参与者中恢复FIX产生; 3）对我们预期用于我们的临床试验的hPPCA载体实施了符合GMP的生产和纯化方法;以及4）与FDA一起定义了获得用于GS基因转移试验的IND所需的剩余临床前研究。在具体目标1中，我们建议生产我们的自身互补rAAV hPPCA载体的临床批次，在具体目标2中，在PPCA小鼠模型中进行最终临床前剂量确定、生物分布和毒性研究。在子目标3.1中，我们已经开始识别和描述半乳糖唾液酸沉积症患者的临床特征和人口统计学特征，目的是识别晚期婴儿型亚组进行基因转移试验。子am 3.2旨在对患有半乳糖唾液酸沉积症的受试者进行拟定的基因转移试验。将监测tril的基因转移证据、PPCA产生的生化证据和疾病临床表现的纠正。

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.