Molecular Pathologies of and Enzyme Replacement Therapies for Lysosomal Diseases

Hitoshi      Sakuraba; Makoto      Sawada; Fumiko      Matsuzawa; Sei-ichi      Aikawa; Yasunori      Chiba; Yoshifumi      Jigami; Kohji      Itoh

Abstract

Lysosomal diseases comprise a group of inherited disorders resulting from defects of lysosomal enzymes and their cofactors, and in many of them the nervous system is affected. Recently, enzyme replacement therapy with recombinant lysosomal enzymes has been clinically available for several lysosomal diseases. Such enzyme replacement therapies can improve non-neurological disorders but is not effective for neurological ones. In this review, we discuss the molecular pathologies of lysosomal diseases from the protein structural aspect, current enzyme replacement therapies, and attempts to develop enzyme replacement therapies effective for lysosomal diseases associated with neurological disorders, i.e., production of enzymes, brain-specific delivery and incorporation of lysosomal enzymes into cells.

Keywords: Lysosomal enzyme, lysosomal disease, Tay-Sachs disease, Sandhoff disease, Fabry disease, protein structure, enzyme replacement therapy, drug delivery