Title:
Chemical chaperone therapy as a novel pharmacological approach for the treatment of neurodegenerative lysosomal storage diseases

Katsumi Higaki, Ph.D.
Associate Professor,
Division of Functional Genomics, Research Center for Bioscience and Technology, Tottori University , Japan

Abstract:
A large number of genetic diseases are caused by enzyme deficiency. The metabolic defect is expressed generally in various tissues and organs, including the central nervous system. Lysosomes are membrane-bound acidic organelles primarily engaged in degradation of various substrates in diverse processes such as endocytosis, phatocytosis and autophagy. They also contain proteins that are involved in the transport of substances into and out of the lumen, acidification of the lysosomal lumen and fusion of the lysosomes with other organelles. Dysfunction of these processes leads to human diseases, lysosomal storage diseases (LSDs). LSDs are a group of inborn errors of metabolism, which encompass more than 60 clinically different entities. They are caused by genetic deficiency of lysosomal functions including hydrolaeses, proteases, lipases, sulfatases or proteins for their synthesis and trafficking, which results in progressive accumulation of undigested substrates in the lysosomes of affected cells. More than half of LSDs exhibit severe progressive neurodegeneration, indicating neurons are vulnerable to lysosomal dysfunction, although the molecular basis for the selective vulnerability remains unknown.
In the past few decades, much progress has been made in the development of therapeutic strategies for LSDs. Enzyme replacement therapy exploits parenteral administration of recombinant enzymes and it has been introduced for the treatment of Gaucher disease and other LSDs. Efficacy of ERT on visceral symptoms has been confirmed in these diseases, but difficulties have been observed in the effects on neurological manifestations. LSDs owing to genetic deficiency of soluble lysoosmal enzymes are generally considered as a promising target of gene therapy, and preclinical trials have been conducted. We have been in pursuit of chemical (or pharmacological) chaperone therapy as an alternative therapeutic approach particulary for the brain pathology of LSDs. In this therapy, competitive enzyme inhibitors with a low molecular weight bind to and stabilize the mutant enzyme protein in the ER and facilitate its transport to the lysosome where it becomes functional. Orally administrated chaperone compounds could reach to the CNS by crossing the blood-brain barrier and ameliorate CNS pathology of GM1-gangliosidosis model mice.
In this talk, I will briefly summarize cellular pathophysiology of the affected cells and the current therapeutic options for LSDs. Then I will show the recent advancement of chemical chaperone therapy for LSDs and discuss the future direction of this strategy.

References:
1. Matsuda J et al, Chemical chaperone therapy for brain pathology in GM1-gangliosidosis. Proc Natl Acad Sci USA , 100(26), 15912-15917, 2003.

2. Suzuki Y et al, Chemical chaperone therapy: clinical effect in murine GM1-gangliosidosis. Ann Neurol, 62(6), 671-675, 2007.

3. Higaki K et al, Chemical chaperone therapy: chaperone effect on mutant enzyme and cellular pathology in b -galactosidase deficiency. Human Mutat, 332(7), 843-852, 2011.

4. Takai T et al, A bicyclic 1-deoxygalactonojirimycin derivative as a novel pharmacological chaperone for GM1 gangliosidosis. Mol Ther, 21(3), 525-532 2013.