The overall objective of the proposed research is to develop gene transfer strategies designed to overcome the three main obstacles to effective neural gene therapy for neuropathic lysosomal storage disease (LSD) with mental retardation. These obstacles are: 1) global neural delivery, 2) neuronal-specific targeting, and 3) continuous neuronal expression. Relevant to this proposal are out previous observations: 1) that the overexpression of human lysosomal enzymes results in their selective secretion, 2) that covalent coupling of neuronotropic polypeptides to lysosomal enzymes markedly enhanced their uptake and endosomal internalization in cultured neurons, and 3) that the blood brain barrier can be transiently and safely opened for neural delivery of macromolecules or enzymes in cats by infusion of hyperosmolar mannitol. The optimal neuronal-targeted overexpression constructs and neural delivery strategies will be assessed in animal models of human LSD in Project 4 of this Program Project.