title: Transgenic rescue of Krabbe disease in the twitcher mouse.
abstract: The twitcher mouse is a natural model of Krabbe disease caused by galactocerebrosidase (GALC) deficiency. Previous attempts at rescuing the twitcher mouse by bone marrow transplantion, viral transduction, or transgenesis were only partially successful. Here, we report the transgenic (tg) rescue of the twitcher mouse with a BAC clone harboring the entire GALC. The twi/twi/hGALC tg mice exhibited growth, motor function, and fertility similar to those of nonaffected animals. These animals had normal levels of GALC activity in brain and were free of the typical twitcher demyelinating pathology. Surprisingly, GALC expression in twi/twi hGALC tg kidneys was low and galactocerebroside storage was only partially cleared. Nonetheless, these mice have been maintained for over 1 year without any sign of disease. Since pathological damage associated with GALC deficiency is confined to the nervous system, our work represents the first successful rescue of the twitcher mouse and opens the possibility of developing novel therapeutic approaches.
authors.affiliation: Department of Psychiatry, Mount Sinai School of Medicine of New York University, New York, NY, USA.
authors.forename: R
authors.initials: R
authors.lastname: De Gasperi
authors.forename: V L
authors.initials: VL
authors.lastname: Friedrich
authors.forename: G M
authors.initials: GM
authors.lastname: Perez
authors.forename: E
authors.initials: E
authors.lastname: Senturk
authors.forename: P H
authors.initials: PH
authors.lastname: Wen
authors.forename: K
authors.initials: K
authors.lastname: Kelley
authors.forename: G A
authors.initials: GA
authors.lastname: Elder
authors.forename: M A
authors.initials: MA
authors.lastname: Gama Sosa
mesh_terms: D000818:Animals; D001483:Base Sequence; D022202:Chromosomes, Artificial, Bacterial; D019976:Cloning, Organism; D004247:DNA / Q000008:administration & dosage*; D005698:Galactosylceramidase / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D007965:Leukodystrophy, Globoid Cell / Q000628:therapy*; D051379:Mice; D008818:Mice, Neurologic Mutants; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010641:Phenotype; D019076:Transgenes; D015053:Zygote / Q000201:enzymology*
chemical_list: D004247:DNA; D005698:Galactosylceramidase