Research in my laboratory is focused on inherited genetic diseases that cause central nervous system dysfunction, with a focus on (1) recessive, childhood onset neurodegenerative disease, in particular the lysosomal storage diseases such as the mucopolysaccharidoses and Battens disease; and (2) dominant genetic diseases for example the CAG repeat disorders, Huntington\'s disease and spinal cerebellar ataxia type I. Our research on childhood onset neurodegenerative diseases is focused on experiments to better understand the biochemistry and cellular trafficking of proteins deficient in these disorders, and to develop gene and cell-based medicines for therapy. Our gene therapy studies are focused on vector development, emphasizing the study of novel envelopes for cellular targeting of lentivirus vectors, or non-traditional capsid proteins for encapsidated vectors (AAV and adenovirus). In recent work we demonstrated that the application of these vectors to animal models of storage disease could reverse CNS deficits. Molecular correlates, examined using gene chip arrays, corroborated the beneficial effects of gene therapy. For cell based therapies, experiments are directed towards understanding the early signaling events required for differentiation of progenitor cell populations using microarray studies coupled with bioinformatics. The proteins revealed are then studied for their roles in development, and for their ability to induce differentiation of endogenous progenitor populations. Therapies for dominant disorders are an exciting challenge and require that the dominant disease allele be silenced. To approach this, we have developed vectors expressing small inhibitory RNA, or siRNA. These small RNAs lead to the degradation of the targeted sequence. We have shown that siRNA reduces expression of the target in cell culture models of CAG repeat diseases, leading to an improved phenotype. Current studies are determining the effectiveness of in vivo delivered siRNA to correct disease manifestations in relevant models.