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.
Department of Internal Medicine, Washington University School of Medicine, Box 8007, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
Darshong
D
Lin
Corinne R
CR
Fantz
Beth
B
Levy
Mohammad A
MA
Rafi
Carole
C
Vogler
David A
DA
Wenger
Mark S
MS
Sands
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