Ambroxol chaperone therapy for neuronopathic Gaucher disease: A pilot study

Gaucher disease (GD) is a lysosomal storage disease characterized by a deficiency of glucocerebrosidase. Although enzyme‐replacement and substrate‐reduction therapies are available, their efficacies in treating the neurological manifestations of GD are negligible. Pharmacological chaperone therapy is hypothesized to offer a new strategy for treating the neurological manifestations of this disease. Specifically, ambroxol, a commonly used expectorant, has been proposed as a candidate pharmacological chaperone. The purpose of this study was to evaluate the safety, tolerability, and neurological efficacy of ambroxol in patients with neuronopathic GD.

[1]  Yoshiyuki Suzuki.  Emerging novel concept of chaperone therapies for protein misfolding diseases , 2014, Proceedings of the Japan Academy. Series B, Physical and biological sciences.

[2]  Y. Maegaki,et al.  Abnormal pupillary light reflex with chromatic pupillometry in Gaucher disease , 2014, Annals of clinical and translational neurology.

[3]  Dianne J. Russell,et al.  Gross Motor Function Measure (GMFM-66 and GMFM-88) User's Manual , 2013 .

[4]  Yoshiyuki Suzuki,et al.  The chaperone activity and toxicity of ambroxol on Gaucher cells and normal mice , 2013, Brain and Development.

[5]  P. Kaplan,et al.  Revised recommendations for the management of Gaucher disease in children , 2013, European Journal of Pediatrics.

[6]  D. Elstein,et al.  Pilot study using ambroxol as a pharmacological chaperone in type 1 Gaucher disease. , 2013, Blood cells, molecules & diseases.

[7]  Noel Southall,et al.  Discovery, structure-activity relationship, and biological evaluation of noninhibitory small molecule chaperones of glucocerebrosidase. , 2012, Journal of medicinal chemistry.

[8]  Ying Sun,et al.  Ex Vivo and in Vivo Effects of Isofagomine on Acid β-Glucosidase Variants and Substrate Levels in Gaucher Disease* , 2011, The Journal of Biological Chemistry.

[9]  F. Sedel,et al.  A French experience of type 3 Gaucher disease: Phenotypic diversity and neurological outcome of 10 patients , 2011, Brain and Development.

[10]  Seon-Yong Jeong,et al.  Clinical and genetic characteristics of Korean patients with Gaucher disease. , 2011, Blood cells, molecules & diseases.

[11]  A. Hartmann,et al.  The neurological manifestations of Gaucher disease type 1: the French Observatoire on Gaucher disease (FROG) , 2010, Journal of Inherited Metabolic Disease.

[12]  Yoshiyuki Suzuki,et al.  Chaperone Activity of Bicyclic Nojirimycin Analogues for Gaucher Mutations in Comparison with N‐(n‐nonyl)Deoxynojirimycin , 2009, Chembiochem : a European journal of chemical biology.

[13]  Yoshitomo Hamuro,et al.  Identification and Characterization of Ambroxol as an Enzyme Enhancement Agent for Gaucher Disease* , 2009, The Journal of Biological Chemistry.

[14]  M. Sasaki,et al.  Reassessment of phenytoin for treatment of late stage progressive myoclonus epilepsy complicated with status epilepticus , 2009, Epilepsy Research.

[15]  R. Schiffmann,et al.  Randomized, controlled trial of miglustat in Gaucher's disease type 3 , 2008, Annals of neurology.

[16]  L. Bour,et al.  Potential efficacy of enzyme replacement and substrate reduction therapy in three siblings with Gaucher disease type III , 2008, Journal of Inherited Metabolic Disease.

[17]  G. Grabowski.  Phenotype, diagnosis, and treatment of Gaucher's disease , 2008, The Lancet.

[18]  P. Alfonso,et al.  Neurologic Improvement in a Type 3 Gaucher Disease Patient Treated with Imiglucerase/Miglustat Combination , 2007, Epilepsia.

[19]  Yoshiyuki Suzuki,et al.  Enzyme enhancement activity of N-octyl -β -valienamine on β-glucosidase mutants associated with Gaucher disease , 2007 .

[20]  Shailendra Giri,et al.  Krabbe disease: psychosine-mediated activation of phospholipase A2 in oligodendrocyte cell death Published, JLR Papers in Press, April 27, 2006. , 2006, Journal of Lipid Research.

[21]  Seiichiro Ogawa,et al.  N-Octyl-β-valienamine up-regulates activity of F213I mutant β-glucosidase in cultured cells: a potential chemical chaperone therapy for Gaucher disease , 2004 .

[22]  J. Allman,et al.  Neuropathology provides clues to the pathophysiology of Gaucher disease. , 2004, Molecular genetics and metabolism.

[23]  Seiichiro Ogawa,et al.  Chemical chaperone therapy for brain pathology in GM1-gangliosidosis , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[24]  M. Herkenham,et al.  Toxicity of glucosylsphingosine (glucopsychosine) to cultured neuronal cells: a model system for assessing neuronal damage in Gaucher disease type 2 and 3 , 2003, Neurobiology of Disease.

[25]  Ernest Beutler,et al.  Chemical chaperones increase the cellular activity of N370S β-glucosidase: A therapeutic strategy for Gaucher disease , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[26]  E. Ginns,et al.  Glucosylsphingosine accumulation in tissues from patients with Gaucher disease: correlation with phenotype and genotype. , 2002, Molecular genetics and metabolism.

[27]  P. Kaplan,et al.  The Gaucher registry: demographics and disease characteristics of 1698 patients with Gaucher disease. , 2000, Archives of internal medicine.

[28]  Kunihiko Suzuki.  Twenty Five Years of the “Psychosine Hypothesis”: A Personal Perspective of its History and Present Status , 1998, Neurochemical Research.

[29]  Satoshi Ishii,et al.  Galactose stabilizes various missense mutants of α-galactosidase in Fabry disease , 1995 .

[30]  Y. Eto,et al.  Characteristics of gene mutations among 32 unrelated Japanese Gaucher disease patients: absence of the common Jewish 84GG and 1226G mutations , 1995, Human Genetics.

[31]  R. Cornell,et al.  Sphingosine inhibits the activity of rat liver CTP:phosphocholine cytidylyltransferase. , 1990, The Journal of biological chemistry.

[32]  Y. Hannun,et al.  Lysosphingolipids inhibit protein kinase C: implications for the sphingolipidoses. , 1987, Science.

[33]  L. Svennerholm,et al.  Accumulation of Glucosylceramide and Glucosylsphingosine (Psychosine) in Cerebrum and Cerebellum in Infantile and Juvenile Gaucher Disease , 1982, Journal of neurochemistry.

[34]  Yoshiyuki Suzuki,et al.  Enzyme enhancement activity of N-octyl-beta-valienamine on beta-glucosidase mutants associated with Gaucher disease. , 2007, Biochimica et biophysica acta.

[35]  J. Jonkman,et al.  Dose-dependent uricosuric effect of ambroxol , 2004, European Journal of Clinical Pharmacology.

[36]  Yoshiyuki Suzuki,et al.  N-octyl-beta-valienamine up-regulates activity of F213I mutant beta-glucosidase in cultured cells: a potential chemical chaperone therapy for Gaucher disease. , 2004, Biochimica et biophysica acta.

[37]  M. Hallett,et al.  The Unified Myoclonus Rating Scale. , 2002, Advances in neurology.

[38]  Satoshi Ishii,et al.  Accelerated transport and maturation of lysosomal α–galactosidase A in Fabry lymphoblasts by an enzyme inhibitor , 1999, Nature Medicine.

[39]  S. Ishii,et al.  Galactose stabilizes various missense mutants of alpha-galactosidase in Fabry disease. , 1995, Biochemical and biophysical research communications.

[40]  C. Granger,et al.  The functional independence measure: a new tool for rehabilitation. , 1987, Advances in clinical rehabilitation.