BackgroundGM1-gangliosidosis is a glycosphingolipid (GSL) lysosomal storage disease caused by a genetic deficiency of acid β-galactosidase (βgal), which results in the accumulation of GM1-ganglioside and its asialo-form (GA1) primarily in the CNS. Age of onset ranges from infancy to adulthood, and excessive ganglioside accumulation produces progressive neurodegeneration and psychomotor retardation in humans. Currently, there are no effective therapies for the treatment of GM1-gangliosidosis.Methodology/Principal FindingsIn this study we examined the effect of thalamic infusion of AAV2/1-βgal vector in adult GM1 mice on enzyme distribution, activity, and GSL content in the CNS, motor behavior, and survival. Six to eight week-old GM1 mice received bilateral injections of AAV vector in the thalamus, or thalamus and deep cerebellar nuclei (DCN) with pre-determined endpoints at 1 and 4 months post-injection, and the humane endpoint, or 52 weeks of age. Enzyme activity was elevated throughout the CNS of AAV-treated GM1 mice and GSL storage nearly normalized in most structures analyzed, except in the spinal cord which showed ∼50% reduction compared to age-matched untreated GM1 mice spinal cord. Survival was significantly longer in AAV-treated GM1 mice (52 wks) than in untreated mice. However the motor performance of AAV-treated GM1 mice declined over time at a rate similar to that observed in untreated GM1 mice.Conclusions/SignificanceOur studies show that the AAV-modified thalamus can be used as a ‘built-in’ central node network for widespread distribution of lysosomal enzymes in the mouse cerebrum. In addition, this study indicates that thalamic delivery of AAV vectors should be combined with additional targets to supply the cerebellum and spinal cord with therapeutic levels of enzyme necessary to achieve complete correction of the neurological phenotype in GM1 mice.

Glioblastoma multiforme (GBM) is a devastating form of brain cancer for which there is no effective treatment. Here, we report a novel approach to brain tumor therapy through genetic modification of normal brain cells to block tumor growth and effect tumor regression. Previous studies have focused on the use of vector-based gene therapy for GBM by direct intratumoral injection with expression of therapeutic proteins by tumor cells themselves. However, as antitumor proteins are generally lethal to tumor cells, the therapeutic reservoir is rapidly depleted, allowing escape of residual tumor cells. Moreover, it has been difficult to achieve consistent transduction of these highly heterogeneous tumors. In our studies, we found that transduction of normal cells in the brain with an adeno-associated virus (AAV) vector encoding interferon-β (IFN-β) was sufficient to completely prevent tumor growth in orthotopic xenograft models of GBM, even in the contralateral hemisphere. In addition, complete eradication of established tumors was achieved through expression of IFN-β by neurons using a neuronal-restricted promoter. To our knowledge this is the first direct demonstration of the efficacy of targeting gene delivery exclusively to normal brain cells for brain tumor therapy.

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