AAV2/5 vector expressing galactocerebrosidase ameliorates CNS disease in the murine model of globoid-cell leukodystrophy more efficiently than AAV2.
Globoid-cell leukodystrophy (GLD) is an autosomal recessive lysosomal storage disorder caused by mutations in the galactosylceramidase (GALC) gene. Infantile GLD has a lethal course with severe cerebral demyelination that progresses to death by 2 years of age. In the current study twitcher mice, an authentic murine model of infantile GLD, were given intracranial injections of either recombinant adeno-associated virus serotype 2 encoding the murine Galc cDNA (AAV2-GALC) or the same genome pseudotyped with AAV5 capsid proteins (AAV2/5-GALC) on day 3 of age. The group injected intracranially with AAV2/5-GALC had approximately 25-fold greater than normal Galc levels in the brain, while AAV2-GALC-injected animals had 28% normal levels. The average life expectancy of twitcher mice ( approximately 38 days) was significantly (P < 0.0001) increased to 48 and 52 days for the AAV2-GALC- and AAV2/5-GALC-treated groups, respectively. The AAV2/5-GALC group performed significantly better in a battery of behavioral tests compared to untreated, AAV2-GFP-treated, or AAV2-treated twitcher animals. This longitudinal study demonstrated that AAV2/5-GALC-mediated gene therapy resulted in higher levels of Galc expression and slowed the neurologic deterioration more completely than AAV2-GALC in the murine model of globoid-cell leukodystrophy. However, the clinical improvements, as assessed by behavioral tests and life span, were only modest.
Lin
Darshong
D
Department of Internal Medicine, Washington University School of Medicine, Box 8007, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
Fantz
Corinne R
CR
Levy
Beth
B
Rafi
Mohammad A
MA
Vogler
Carole
C
Wenger
David A
DA
Sands
Mark S
MS
D000818:Animals; D001522:Behavior, Animal; D001835:Body Weight; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002493:Central Nervous System Diseases / Q000201:enzymology* / Q000235:genetics; D018076:DNA, Complementary / Q000378:metabolism; D000229:Dependovirus / Q000235:genetics*; D004195:Disease Models, Animal; D005698:Galactosylceramidase / Q000235:genetics*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000295:instrumentation* / Q000379:methods; D005822:Genetic Vectors / Q000235:genetics*; D005838:Genotype; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006720:Homozygote; D007965:Leukodystrophy, Globoid Cell / Q000628:therapy*; D051379:Mice; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D010641:Phenotype; D016133:Polymerase Chain Reaction; D013997:Time Factors
D018076:DNA, Complementary; D049452:Green Fluorescent Proteins; D005698:Galactosylceramidase