Concept and Development of Chaperone Therapy for Protein Misfolding Diseases

Chaperone t herapy i s a n ew co ncept o f m olecular t herapeutic approach m ainly d eveloped f or l ysosomal d iseases, b ased o n a p aradoxical molecular interaction involving a mutant en zyme and its competitive in hibitor as an intracellular en hancer ( chaperone). T he misfolded mutant pr otein is transported safely to the lysosome as a co mplex with a specific chaperone. The enzyme act ivity i s ex pressed a fter di ssociation f rom i ts c haperone. T he advantages of this molecular therapeutic approach can be summarized twofold; first, o ral a dministration t o i ndividuals w ith i ntractable di seases; a nd s econd, delivery t o t he c entral ne rvous s ystem f or t reatment of br ain dy sfunction. I n recent y ears t he ch aperone t herapy r esearch h as b een w idely d eveloped f or various protein misfolding diseases as well as lysosomal diseases. In this article, recent progress of chaperone therapy for lysosomal diseases is briefly reviewed, mainly focusing on GM1-gangliosidosis and Morquio B disease (β-galactosidase deficiency) an d G aucher d isease ( β-glucosidase deficiency) as r epresentative neurogenetic diseases.