ENZYME REPLACEMENT THERAPY IN LYSOSOMAL STORAGE DISORDERS

There are several strategies for the treatment of inborn errors of metabolism: Removal of toxic substrates is effective in disturbances of amino acid metabolism (e.g. phenylketonuria). Effective replacement of genetically deficient enzymes in metabolic disorders (particularly in lysosomal storage disorders) requires targeting of the enzyme to specific cells. Targeting can be achieved by entrapment of the enzyme into liposomes or by incorporation into red cell ghosts. While these efforts have not been rewarding, great success has been achieved in Gaucher disease by using modified beta-glucocerebrosidase: Careful removal of glycosidic side chains facilitates uptake of the enzyme by the storage cells (macrophages). Effective treatment of neurodegenerative lysosomal storage disorders by exogenous enzyme supply is hindered by the blood-brain barrier. In an animal model it has been demonstrated that effective lysosomal targeting of the enzyme Hexosaminidase A could be obtained by coupling it to an atoxic fragment of tetanus toxin.