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Feline ganglioside storage diseases are authentic models of the human conditions and are valuable for development of gene therapy strategies for human patients. Deficiency of the lysosomal enzymes |[beta]|-galactosidase or |[beta]|-N-acetylhexosaminidase causes continuous cumulation of GM1 or GM2 ganglioside, respectively, resulting in disease manifestations nd death. There is no reliable treatment for human gangliosidoses, although knockout mouse models have been used to develop promising experimental treatments including gene therapy with adeno-associated virus vectors. Intracranial injection of GM1 knockoutenetic background (FVB-Twi), that we generated based on previous indications on the effects of the genetic background in modulating GLD severity (Tominaga K. et al., J. Neurosci. Res. 2004; Biswas S. et al., Neurobiol. of Disease 2002); ii) a mouse with low GALC activity, recently generated in D. Wenger's laboratory by introducing in the murine GALC gene a polymorphism that was found in individuals having some not otherwise explainable neurological abnormalities in the presence of 10|[ndash]|20% residual GALC activity, the trs mouse (Luzi P. et al., Mol. Genetics and Metab. 2001). These three models showed some substantial differences in their phenotype and mice has achieved supranormal levels of |[beta]|-galactosidase throughout the brain, with lower levels of |[beta]|-galactosidase activity observed at distant sites including retina and spinal cord (M. Sena-Esteves, unpublished data). Similarly, intracranial injection of GM2 knockout mice has produced widespread expression of hexosaminidase activity, substantially decreased storage of GM2 ganglioside and life spans significantly increased to greater than three times that of untreated GM2 mice (see abstract by Cachon-Gonzalez at this meeting). To investigate the potential for adeno-associated virus treatment of human patients, well-characterized feline models of gangliosidoses were treated with vectors proven to be successful in mice. After intracranial injections of vector through a single needle track, enzymatic activity was detected throughout the injected hemisphere, with high levels at the injection site and gradually decreasing but substantial enzymatic activity at least 1 cm cranial and caudal to the point of injection. Enzymatic activity also was detected in the cerebral cortex of the contralateral hemisphere. In addition, staining for storage material with the periodic acid-Schiff (PAS) reagent indicated that decreased ganglioside content coincided with increased levels of enzymatic activity. Detailed results of these studies will be presented.