Gene Transfer for Galactosialidosis - Resub

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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.