Sustained normalization of neurological disease after intracranial gene therapy in a feline model.
Progressive debilitating neurological defects characterize feline G(M1) gangliosidosis, a lysosomal storage disease caused by deficiency of lysosomal β-galactosidase. No effective therapy exists for affected children, who often die before age 5 years. An adeno-associated viral vector carrying the therapeutic gene was injected bilaterally into two brain targets (thalamus and deep cerebellar nuclei) of a feline model of G(M1) gangliosidosis. Gene therapy normalized β-galactosidase activity and storage throughout the brain and spinal cord. The mean survival of 12 treated G(M1) animals was >38 months, compared to 8 months for untreated animals. Seven of the eight treated animals remaining alive demonstrated normalization of disease, with abrogation of many symptoms including gait deficits and postural imbalance. Sustained correction of the G(M1) gangliosidosis disease phenotype after limited intracranial targeting by gene therapy in a large animal model suggests that this approach may be useful for treating the human version of this lysosomal storage disorder.
Scott-Ritchey Research Center, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA.
Victoria J
VJ
McCurdy
Aime K
AK
Johnson
Heather L
HL
Gray-Edwards
Ashley N
AN
Randle
Brandon L
BL
Brunson
Nancy E
NE
Morrison
Nouha
N
Salibi
Jacob A
JA
Johnson
Misako
M
Hwang
Ronald J
RJ
Beyers
Stanley G
SG
Leroy
Stacy
S
Maitland
Thomas S
TS
Denney
Nancy R
NR
Cox
Henry J
HJ
Baker
Miguel
M
Sena-Esteves
Douglas R
DR
Martin
D000818:Animals; D001921:Brain / Q000473:pathology*; D001947:Breeding; D002415:Cats; D000229:Dependovirus / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D015316:Genetic Therapy; D006801:Humans; D008247:Lysosomes / Q000201:enzymology; D008279:Magnetic Resonance Imaging; D008297:Male; D009422:Nervous System Diseases / Q000628:therapy*; D009928:Organ Specificity; D016019:Survival Analysis; D001616:beta-Galactosidase / Q000235:genetics / Q000627:therapeutic use
D001616:beta-Galactosidase