Gene Transfer for Galactosialidosis - Resub

描述(申请人提供)：该项目致力于半乳糖化病(GS)基因治疗的发展，GS是一种常染色体隐性遗传性溶酶体储存疾病，属于糖蛋白沉积症亚型。GS是由溶酶体羧肽酶、保护蛋白/组织蛋白酶A的初级缺陷引起的，导致β-半乳糖苷酶和神经氨酸酶的继发性联合缺陷。基因转移的最初参与者将是具有晚期婴儿表型的个体，这些个体存活到童年和 青春期是常见的，没有伴随的神经体征，允许躯体表型逆转具有很高的潜在临床相关性。我们在以下方面取得了进展：1)开发了一种新型的编码-/-PPCA的rAAV自互补载体，并证明它可以纠正GS(PPCA)小鼠模型中的表型；2)证明了编码人凝血因子IX的类似rAAV载体可以恢复血友病B临床试验参与者的固定生产；3)对我们预期在临床试验中使用的hPPCA载体实施了符合GMP的生产和纯化方法；以及4)与FDA定义了剩余的临床前研究，以获得针对GS的基因转移试验所需的IND。在特定目标1中，我们建议生产大量临床上自互补的rAAV hPPCA载体，并在特定目标2中在PPCA小鼠模型中进行最终的临床前剂量发现、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表征半乳唾液酸中毒患者的临床特征和人口学特征，目标是识别出一个婴儿晚期亚群，用于基因转移试验。SUB-AM 3.2将为患有乳汁淤积症的参与者进行拟议的基因转移试验。将监测TRIL，以寻找基因转移的证据，PPCA产生的生化证据，以及纠正这种疾病的临床表现。

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.