Therapeutic chaperone effect of N-Octyl 4-Epi-β-valienamine on murine G M1 -gangliosidosis Yoshiyuki Suzuki a, ⁎, Satoshi Ichinomiya a, c , Mieko Kurosawa b , Junichiro Matsuda d , Seiichiro Ogawa e , Masami Iida f , Takatoshi Kubo f , Miho Tabe g , Masayuki Itoh h , Katsumi Higaki i , Eiji Nanba i , Kousaku Ohno j a Graduate School, International University of Health and Welfare, Otawara,Japan b Center for Medical Science, International University of Health and Welfare, Otawara,Japan c Department of Rehabilitation, Otawara Red Cross Hospital, Otawara,Japan d Biological Resource Division, National Institute of Biomedical Innovation, Ibaraki City, Osaka,Japan e Department of Biosciences and Informatics, Faculty of Science and Technology, Keio University, Yokohama, Japan f Central Research Laboratories, Seikagaku Corporation, Higashi-Yamato, Japan g Biochemistry Section, Analysis Center for Medical Science, SRL Inc, Hachioji,Japan h Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira,Japan i Division of Functional Genomics, Research Center for Bioscience and Technology, Tottori University, Yonago,Japan j Division of Child Neurology, Faculty of Medicine, Tottori University, Yonago,Japan a b s t r a c t a r t i c l e i n f o Article history: Received 9 January 2012 Received in revised form 21 February 2012 Accepted 21 February 2012 Available online 3 March 2012 Keywords: Chaperone therapy GM1-gangliosidosis β-Galactosidase N-octyl 4-epi-β-valienamine NOEV Therapeutic chaperone effect of a valienamine derivative N-octyl 4-epi-β-valienamine (NOEV) was studied in G M1 -gangliosidosis model mice. Phamacokinetic analysis revealed rapid intestinal absorption and renal ex- cretion after oraladministration.Intracellular accumulation was not observed after continuous treatment. NOEV was delivered to the central nervous system through the blood–brain barrier to induce high expression of the apparently deficient β-galactosidase activity. NOEV treatment starting at the early stage of disease resulted in remarkable arrest of neurological progression within a few months. Survival time was signi ficant- ly prolonged.This result suggests that NOEV chaperone therapy will be clinically effective for prevention of neuronal damage if started early in life hopefully also in human patients with G M1 -gangliosidosis. © 2012 Elsevier Inc. All rights reserved. 1. Introduction G M1 -gangliosidosis (OMIM 230500) is one of the lysosomal diseases caused by mutations of the gene GLB1 coding for β-galactosidase (β-gal) (EC 3.2.1.23) [1] with storage of ganglioside G M1 , keratan sulfate, and glycoprotein-derived oligosaccharides, presenting clinically with pro- gressive neurological deterioration mainly in infancy (infantile form) and childhood (juvenile form), and rarely in adults (adult form) [2]. Morquio B disease (OMIM 253010) is another rare disease with skeletal manifestations without involvementof the centralnervous system. These clinicalforms are caused by different mutations ofthe same gene GLB1 [3,4]. There is a correlation between the residual enzyme ac- tivity and severity of clinical phenotype, particularly the age of onset [5]. This finding led us to search for a molecular strategy to restore the ap- parently lost function of the mutant enzyme molecule. Soon a molecular instability was found in some mutant enzymes at relatively high envi- ronmental temperature and high pH [6,7]. Then a paradoxical phenomenon was found wherein a high amount of free galactose enhanced remarkably the intracellular mutant α- galactosidase A enzyme activity in cultured lymphoblasts from Fabry disease patients [8]. This observation was confirmed in a short-term human experiment [9]. A galactose analog 1-deoxygalactonojirimycin (DGJ) also was found to be effective in Fabry disease cells and tissues [10].We concluded that low molecular weight competitive inhibitors could serve as chemical chaperones to induce expression of catalytic ac- tivities of mutant enzymes after stabilization and successful intracellular transport to the lysosome in somatic cells [11]. Subsequently we developed two derivatives of a newly synthe- sized organic compound valienamine, N-octyl 4-epi-β-valienamine (NOEV) and its epimer N-octyl β-valienamine as chemical chaper- ones for mutant β-galactosidase and β-glucosidase proteins, respec- tively,to restore the enzyme activities in somatic cells from patients with G M1 -gangliosidosis and Gaucher disease [12,13]. We focused our interest on NOEV for treatment and prevention of brain damage Molecular Genetics and Metabolism 106 (2012) 92–98 Abbreviations: β-gal, β-galactosidase; NOEV, N-octyl 4-epi-β-valienamine; DGJ, 1- deoxygalactonojirimycin; WT, wild type; KO, knockout; Tg, transgenic; LC, liquid chro- matography; MS/MS, tandem mass spectrometry; LLOQ, lower limit of quantification; GOT, glutamic-oxalacetic transaminase; GPT, glutamic-pyruvic transaminase; BUN, blood urea nitrogen; PBS, phosphate-buffered saline; BSA, bovine serum albumin. ⁎ Corresponding author at: International University of Health and Welfare, Graduate School,2600-1 Kita Kanemaru, Otawara 324-8501, Japan.Fax: +81 287 24 3229. E-mail address: suzukiy@iuhw.ac.jp (Y. Suzuki). 1096-7192/$ – see front matter © 2012 Elsevier Inc. 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