Novel Neuronal Transport Mechanisms of Lyosomal Enzymes

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DESCRIPTION (provided by applicant): Cognitive deficits due to the accumulation of storage material in the brain can be the most severe clinical signs associated with lysosomal storage diseases. The CNS defects are also difficult to treat. We recently injected an AAV vector directly into the vitreous of the eye in the murine model of mucopolysaccharidosis type VII (MPS VII). High levels of GUSB activity were observed in the retina and in the optic nerve. We also discovered GUSB activity in the brains of NTS VII mice. GUSB activity was detected primarily in the visual tracts, specifically the lateral geniculate and superior colliculus. Interestingly, the reduction of lysosomal storage material extended beyond the visual system and into the hippocampus and cerebral cortex. Therefore, this approach may represent a less invasive method of delivering therapeutic levels of a lysosomal enzyme into the brain. The goals of this project are to determine the distribution of wild type and modified GUSB and the extent of histopathologic correction in both the mouse and canine models of MPS VII. We will also determine if the transport of a lysosomal enzyme from the eye to the brain with a reduction of storage is common to another lysosomal storage disease. We will accomplish these goals with the following Specific Aims. 1) We will determine the distribution of both native and modified GUSB, and the extent of lysosomal storage reduction in the CNS of the murine model of MPS VII following intravitreal injection of a gene transfer vector. 2) We will determine the distribution of both native and modified GUSB, and the extent of lysosomal Storage reduction in the CNS of the canine model of MPS VII following intravitreal injection of a gene transfer vector. 3) We will determine the distribution of palmitoyl protein thioesterase 1 and the effect on lysosomal storage in the brain of the murine model of infantile neuronal ceroid lipofuscinosis following intravitreal injection of a gene transfer vector.