Important advances have been made recently in the development of methods for treating human lysosomal enzyme deficiency diseases. Studies proposed in this application will augment and extend this progress by utilizing feline GM1 gangliosidosis as a model of human lysosomal diseases for in vitro and in vivo studies of enzyme replacement therapy. Specific problems to be investigated include: (a) Evaluation of the ability of cells to recover from prolonged dysfunction, following correction of the metabolic defect by enzyme therapy; (b) Elucidation of the factors which influence uptake and metabolic utilization of exogenous enzyme by mutant tissues; (c) Investigation of lysosomal hydrolase administration techniques which may overcome therapeutic limitations imposed by the blood-brain barrier; (d) Development of "packaging" techniques or molecular modification of exogenous enzyme to facilitate stability, uptake and hydrolytic function; and (e) Definition of any deleterious consequences of repeated administration of purified exogenous lysosomal hydrolases. This model system provides optimal conditions for exploration of these questions, and it is anticipated that results of these studies will form the basis for clinical application of safe, effective therapeutic measures in patients afflicted with these devastating diseases.