Fibroblast screening for chaperone therapy in beta-galactosidosis.

Abstract

We performed screening of beta-galactosidase-deficient fibroblasts for possible chemical chaperone therapy using N-octyl-4-epi-beta-valienamine (NOEV) in patients with GM1-gangliosidosis and Morquio B disease (beta-galactosidosis). Fibroblasts were cultured with NOEV for 4 days and beta-galactosidase activity was measured. Mutation analysis was performed simultaneously. Two separate criteria were set for evaluation of the chaperone effect: a relative increase of enzyme activity (more than 3-fold), and an increase up to more than 10% normal enzyme activity. Among the 50 fibroblast strains tested, more than 3-fold increase was achieved in 17 cell strains (34%), and more than 10% normal activity in 10 (20%). Both criteria were satisfied in 6 (12%), and either of them in 21 (42%). Juvenile GM1-gangliosidosis was most responsive, and then infantile GM1-gangliosidosis. This enhancement was mutation-specific. We estimate that the NOEV chaperone therapy will be effective in 20-40% of the patients, mainly in juvenile and infantile GM1-gangliosidosis patients. A molecular design may produce mutation-specific chaperone compounds for the other disease phenotypes. This cellular screening will be useful for identification of human patients with beta-galactosidase deficiency for chaperone therapy to be started in the near future.

• Authors: Hiroyuki Iwasaki, Hiroshi Watanabe, Masami Iida, Seiichiro Ogawa, Miho Tabe, Katsumi Higaki, Eiji Nanba, Yoshiyuki Suzuki
• Journal: Brain & development (Brain Dev) Vol. 28 Issue 8 Pg. 482-6 (Sep 2006) ISSN: 0387-7604 [Print] Netherlands
• PMID: 16617000 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cyclohexenes
• Hexosamines
• Molecular Chaperones
• Glutamine
• valienamine
• Arginine
• beta-Galactosidase

Topics

• Arginine (genetics)
• Cells, Cultured
• Cyclohexenes
• Dose-Response Relationship, Drug
• Drug Evaluation, Preclinical (methods)
• Fibroblasts (drug effects)
• Gangliosidosis, GM1 (genetics, pathology)
• Genotype
• Glutamine (genetics)
• Hexosamines (pharmacology, therapeutic use)
• Humans
• Molecular Chaperones (pharmacology, therapeutic use)
• Mucopolysaccharidosis IV (genetics, pathology)
• Mutation
• Phenotype
• beta-Galactosidase (genetics, metabolism)