Enzyme replacement therapy results in substantial improvements in early clinical phenotype in a mouse model of globoid cell leukodystrophy.

Abstract

Globoid cell leukodystrophy (GLD) or Krabbe disease is a devastating, degenerative neurological disorder caused by mutations in the galactosylceramidase (GALC) gene that severely affect enzyme activity. Currently, treatment options for this disorder are very limited. Enzyme replacement therapy (ERT) has been shown to be effective in lysosomal storage disorders with predominantly peripheral manifestations such as type I Gaucher's and Fabry's disease. Little however is known about the possible benefit of ERT in GLD, which has a substantial central nervous system component. In this study, we examined the effect of peripheral GALC injections in the twitcher mouse model of the disease. Although we were unable to block the precipitous decline that normally occurs just before death, we did observe significant early improvements in motor performance, a substantial attenuation in the initial failure to thrive, and an increase in life span. Immunohistochemical and activity analyses demonstrated GALC uptake in multiple tissues, including the brain. This was associated with a decrease in the abnormal accumulation of the GALC substrate psychosine, which is thought to play a pivotal role in disease pathology. These results indicate that peripheral ERT is likely to be beneficial in GLD.

• Authors: Wing C Lee, Andrew Courtenay, Frederick J Troendle, Melody L Stallings-Mann, Chad A Dickey, Michael W DeLucia, Dennis W Dickson, Christopher B Eckman
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 19 Issue 11 Pg. 1549-51 (Sep 2005) ISSN: 1530-6860 [Electronic] United States
• PMID: 15987783 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Recombinant Proteins
• Psychosine
• Galactosylceramidase

Topics

• Animals
• Blood-Brain Barrier
• Cell Line
• Disease Models, Animal
• Failure to Thrive (drug therapy)
• Gait (drug effects)
• Galactosylceramidase (analysis, therapeutic use)
• Humans
• Immunohistochemistry
• Leukodystrophy, Globoid Cell (drug therapy, enzymology)
• Mice
• Mice, Inbred C57BL
• Phenotype
• Psychosine (analysis)
• Recombinant Proteins (therapeutic use)