Development of pharmacological chaperone therapy for central nervous system impairment in lysosomal storage disorders
Aya Narita
Assistant professor
Department of Child Neurology, Tottori University Hospital
Abstract
Lysosomal storage disorders (LSDs) are inborn errors of metabolism caused by genetic defects of acid hydrolytic enzymes contained in lysosomes, which are intracellular organelles responsible for intracellular digestion and recycling of macromolecules. There are currently more than 60 established forms of LSDs, many of which present with progressive central nervous system (CNS) impairement. Although therapies such as enzyme replacement therapy, substrate reduction therapy, and hematopoietic stem cell transplantation are now in clinical application, their therapeutic effects on CNS are poor and therapeutic development is long overdue.
Gaucher disease is one of the common LSD caused by a mutation of the glucocerebrosidase (GBA) gene, which results in decreased activity or deficiency of GBA. Enzyme replacement therapy and substrate reduction therapy have been approved in Japan, but neither has any effect on CNS symptoms. Pharmacological chaperone therapy is a therapeutic strategy for neurological symptoms that aims to restore enzyme activity by administering small molecule compounds with properties that promote proper folding and stabilization of the mutant enzyme protein. This presentation will outline the principles and clinical development of pharmacological chaperone therapy for LSDs.
References
