Chaperone Therapy: New Molecular Therapy for Protein Misfolding Diseases with Brain Dysfunction

Chaperone therapy was proposed as a new molecular therapeutic approach almost simultaneously to lysosomal diseases and cystic fibrosis, caused by gene mutations resulting in misfolding of expressed proteins. In our original papers, we reported that unstable mutant lysosomal enzymes causing lysosomal diseases resulted in rapid intracellular degradation and loss of catalytic function. However, in the presence of some low molecular competitive inhibitors (chemical chaperones), after binding to enzyme active sites, paradoxically stabilized and enhanced catalytic activities in somatic cells (proteostasis) by correcting the enzyme protein folding. After oral administration, they were transferred to the bloodstream, reached the brain tissue through the blood-brain barrier, and normalized pathophysiology of the disease. Our reports of these inhibitory chaperones were followed by reports of non-competitive (or allosteric) chaperones without inhibitory bioactivity. Furthermore heat shock proteins and other endogenous proteins were recognized as candidates for the third-type chaperone therapy. Theoretically they could be utilized for handling abnormally accumulated intracellular mutant proteins, if they are overexpressed by small molecules particularly in neurodegenerative diseases. These three types of chaperone therapies are expected as promising approaches to a variety of diseases, genetic or nongenetic, and neurological or non-neurological, in addition to lysosomal diseases. Finally, in this article, possible chaperones for Gaucher disease are discussed, and preliminary clinical results of ambroxol therapy are summarized.