Recent Advances in Enzyme Replacement Therapy for Lysosomal Diseases

Abstract

Lysosomal diseases are inherited metabolic disorders caused by gene defects of lysosomal enzymes and their cofactors, which are characterized by the accumulation of undegraded natural substrates, including glycoconjugates, in lysosomes. The patients develop quite heterogeneous and progressive manifestations, and most of them involve neurological symptoms. In recent years, enzyme replacement therapy (ERT) with recombinant lysosomal enzymes has been clinically available for several non-neurological diseases, such as Gaucher disease type 1, Fabry disease cardiac type, and Pompe disease, on the basis of the endocytotic mechanism through binding of the mannose-6-phosphate- and mannose residues-containing oligosaccharides attached to lysosomal enzymes to the cation-independent mannose-6-phosphate receptor (CI-M6PR) and mannose receptor (MR) as molecular targets in visceral organs of the patients as well as delivery to lysosomes. However, two major problems are present in the clinical application of the ERT for lysosomal diseases. One is the difficulty in producing a large amount of recombinant human enzymes inexpensively. The other is the inefficiency for neurological diseases because intravenously administered enzymes cannot be incorporated into the central nervous system (CNS) across the blood-brain barrier (BBB).