Major advances have been made in the biochemical and pathophysiologic understanding of metabolic diseases during the past decade. Sophisticated chemical and enzymatic techniques as well as in vitro tissue culture systems have been developed to identify the specific metabolic defects in over 100 of these disorders. Utilization of these techniques in major centers has made the diagnosis of these disorders a reality. However, these patients and their families have become increasingly disappointed by the absence of specific therapy in most. This proposal is designed to investigate the potential of enzyme replacement therapy. The therapeutic effectiveness of enzyme replacement by the transplantation of enzyme-producing tissues and by the injection of purified, stabilized human enzyme will be determined. The system for evaluation of these therapies will be limited to those disorders in which specific enzyme defects have been characterized. Initially, Fabry's disease, a disorder characterized by the cardiovascular-renal lipid deposition resulting from the defective enzyme, alpha-galactosidase A, will be the focuse of these studies. Enzyme therapy in this disorder by renal transplantation has been undertaken; further studies will be directed to elucidate the mechanism of enzyme transplantation and to evaluate long term clinical and biochemical effectiveness. Cultured skin fibroblasts deficient in alpha-galactosidase A activity will provide a model system to investigate the therapeutic potential of various purified and stabilized enzyme preparations prior to clinical trials of insulin-like replacement therapy. These in vivo and in vitro studies will be evaluated by careful biochemical measurements of enzyme and substrate levels as well as planned clinical assessment. Successful therapy of this disorder may provide the basis for the specific treatment of other metabolic disorders.