In a collaborative study with investigators at the University of Oxford, UK, we are examining the effects of small molecular weight inhibitors of the formation of globotriaosylceramide in the murine analogue of Fabry disease created by scientists in DMNB and NIDCR. If these molecules prove effective in this model, their clinical effects will be evaluated in patients with Fabry disease. Since these molecules can cross the blood-brain barrier, it is anticipated that an investigation of the effect of inhibiting the formation of glucocerebroside and the toxic de-acylated derivative glucopsychosine, will be undertaken in patients with the neuronopathic forms of Gaucher disease.We have shown that bone-marrow transplantation causes a reduction of stored globotriaosylceramide in most of the organs and tissues of the murine model of Fabry disease. Bone-marrow stem and progenitor cells derived from patients with Fabry disease transduced with a retrovirus containing the human cDNA for alpha-galactosidase A are functionally corrected, and they express the enzyme for a long period of time. Moreover, the corrective alpha-galactosidase A is taken up by non-transduced bystander cells, and it is present in the circulation of experimental animals over an extended period. These experiments provide considerable incentive for gene therapy trials in patients with Fabry disease with transduced hematopoietic stem cells and bone-marrow mesenchymal stem cells. - Fabry Disease, Gaucher Disease; Inhibition of Sphingoglycolipid Formation; Gene Therapy - Human Subjects

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Intramural Research (Z01)
Project #
1Z01NS002984-01
Application #
6228075
Study Section
Special Emphasis Panel (DMNB)
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
City
State
Country
United States
Zip Code
Mochel, Fanny; Boildieu, Nadège; Barritault, Julie et al. (2010) Elevated CSF N-acetylaspartylglutamate suggests specific molecular diagnostic abnormalities in patients with white matter diseases. Biochim Biophys Acta 1802:1112-7
Mochel, Fanny; Yang, Bingzhi; Barritault, Julie et al. (2009) Free sialic acid storage disease without sialuria. Ann Neurol 65:753-7
Goker-Alpan, Ozlem; Wiggs, Edythe A; Eblan, Michael J et al. (2008) Cognitive outcome in treated patients with chronic neuronopathic Gaucher disease. J Pediatr 153:89-94
Shen, Jin-Song; Meng, Xing-Li; Moore, David F et al. (2008) Globotriaosylceramide induces oxidative stress and up-regulates cell adhesion molecule expression in Fabry disease endothelial cells. Mol Genet Metab 95:163-8
Moore, David F; Goldin, Ehud; Gelderman, Monique P et al. (2008) Apoptotic abnormalities in differential gene expression in peripheral blood mononuclear cells from children with Fabry disease. Acta Paediatr Suppl 97:48-52
Benko, W S; Hruska, K S; Nagan, N et al. (2008) Uniparental disomy of chromosome 1 causing concurrent Charcot-Marie-Tooth and Gaucher disease Type 3. Neurology 70:976-8
Schiffmann, Raphael; Fitzgibbon, Edmond J; Harris, Chris et al. (2008) Randomized, controlled trial of miglustat in Gaucher's disease type 3. Ann Neurol 64:514-22
Moore, David F; Ries, Markus; Forget, Evelyn L et al. (2007) Enzyme replacement therapy in orphan and ultra-orphan diseases: the limitations of standard economic metrics as exemplified by Fabry-Anderson disease. Pharmacoeconomics 25:201-8
Schiffmann, Raphael; Askari, Hasan; Timmons, Margaret et al. (2007) Weekly enzyme replacement therapy may slow decline of renal function in patients with Fabry disease who are on long-term biweekly dosing. J Am Soc Nephrol 18:1576-83
Ries, M; Kim, H J; Zalewski, C K et al. (2007) Neuropathic and cerebrovascular correlates of hearing loss in Fabry disease. Brain 130:143-50

Showing the most recent 10 out of 110 publications