Gene Therapy of the Gangliosidoses

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DESCRIPTION (provided by applicant): The overarching goal of this project is to evaluate the application of virally vectored gene therapy of the gangliosidoses for efficacy and safety using state of the art lentiviral and adeno-associated viral vectors in a well characterized, authentic feline model of human GM1 gangliosidoses. Fatal neuronopathic lysosomal diseases must be treated at the earliest time possible to prevent or reverse the neurological component of these disorders. Therefore, we will evaluate transfection of central nervous system (CNS) and non-CNS organs after administration of viral vectors in utero and very early postnatally. Vectors expressing marker or therapeutic genes will be injected in the brain or systemically in fetal kittens at 25-50 days of gestation or perinatal kittens 2-6 weeks old. Normal kittens will be evaluated for expression and distribution of vectored marker genes to provide the essential biological characteristics used to optimize therapy. Kittens with GM1 gangliosidoses will be treated in utero and postnatally with vectors expressing lysosomal beta-galactosidase and evaluated for progression of neurological and systemic disease using a variety of morphological, biochemical and molecular methods. Assessment of disease status in liver and thymus will provide comparison between systemic and CNS responses. Mechanisms by which gene therapy may alter the course of the gangliosidoses by direct transfection of enzyme deficient cells or cross correction by enzyme donor cells, will be studied in vitro and in vivo. Adverse reactions to viral vectors and transgenes will be monitored carefully. The results of this work will provide basic understanding of the potential benefits and risks resulting from gene therapy of lysosomal diseases and other global degenerative diseases of the nervous system. This preclinical study will generate essential information leading to the translation of gene therapy to children with neuronopathic lysosomal diseases.