BONE-MARROW TRANSPLANTATION CORRECTS THE ENZYME DEFECT IN NEURONS OF THE CENTRAL-NERVOUS-SYSTEM IN A LYSOSOMAL STORAGE DISEASE

Neuronal storage disorders are fatal neuro-degenerative diseases of hu mans and animals that are caused by inherited deficiencies of lysosoma l hydrolase activity. Affected individuals often appear normal at birt h but eventually develop progressive neurologic symptoms including sen sory and motor deficits, mental retardation, and seizures. We have exa mined efficacy of bone marrow transplantation as a means of enzyme rep lacement, using cats with the lysosomal storage disease alpha-mannosid osis. Treated animals showed little or no progression of neurologic si gns 1-2 years after transplant, whereas untreated cats became severely impaired and reached end-stage disease by 6 months of age. Increased lysosomal alpha-mannosidase activity was found in brain tissue of the treated animals, and electron microscopy revealed no evidence of lysos omal storage within most neurons. Histochemical localization of acidic alpha-D-Mannoside mannohydrolase (EC 3.2. 1.24), using 5-bromo-4-chlo ro-3-indolyl alpha-D-mannopyranoside, showed that functional enzyme wa s present in neurons, glial cells, and cells associated with blood ves sels. This study provides direct evidence that bone marrow transplanta tion as treatment for a neuronal storage disease can lead to significa nt levels of a missing lysosomal hydrolase within neurons of the centr al nervous system and to compensation for the genetic metabolic defect .