Chemical Chaperone Therapy for Brain Pathology in GM1-Gangliosidosis

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 100; no. 26; pp. 15912 - 15917
• Main Authors: Matsuda, Junichiro, Suzuki, Osamu, Oshima, Akihiro, Yamamoto, Yoshie, Noguchi, Akira, Takimoto, Kazuhiro, Itoh, Masayuki, Matsuzaki, Yuji, Yasuda, Yosuke, Ogawa, Seiichiro, Sakata, Yuko, Nanba, Eiji, Higaki, Katsumi, Ogawa, Yoshimi, Tominaga, Lika, Ohno, Kousaku, Iwasaki, Hiroyuki, Watanabe, Hiroshi, Brady, Roscoe O., Suzuki, Yoshiyuki
• Format: Journal Article
• Language: English
• Published: National Academy of Sciences 23.12.2003; National Acad Sciences
• Subjects: Biological Sciences; Brain; Central nervous system diseases; Enzymes; Fabry disease; Fibroblasts; Gangliosides; Gaucher disease; Mucopolysaccharidosis IV; Nervous system diseases; Neurons
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2536657100

We synthesized a galactose derivative, N-octyl-4-epi-β-valienamine (NOEV), for a molecular therapy (chemical chaperone therapy) of a human neurogenetic disease, β-galactosidosis (GM1-gangliosidosis and Morquio B disease). It is a potent inhibitor of lysosomal β-galactosidase in vitro. Addition of NOEV in the culture medium restored mutant enzyme activity in cultured human or murine fibroblasts at low intracellular concentrations, resulting in a marked decrease of intracellular substrate storage. Short-term oral administration of NOEV to a model mouse of juvenile GM1-gangliosidosis, expressing a mutant enzyme protein R201C, resulted in significant enhancement of the enzyme activity in the brain and other tissues. Immunohistochemical stain revealed a decrease in the amount of GM1and GA1in neuronal cells in the fronto-temporal cerebral cortex and brainstem. However, mass biochemical analysis did not show the substrate reduction observed histochemically in these limited areas in the brain probably because of the brief duration of this investigation. Chemical chaperone therapy may be useful for certain patients with β-galactosidosis and potentially other lysosomal storage diseases with central nervous system involvement.