CNS-directed AAV2-mediated gene therapy ameliorates functional deficits in a murine model of infantile neuronal ceroid lipofuscinosis.
The neuronal ceroid lipofuscinoses (Batten disease) are a group of inherited neurodegenerative diseases characterized by the progressive intralysosomal accumulation of autofluorescent material in many cells, visual defects, seizures, cognitive deficits, and premature death. Infantile neuronal ceroid lipofuscinosis (INCL) has the earliest onset ( approximately 1.5 years of age) and is caused by a deficiency in the lysosomal enzyme palmitoyl protein thioesterase-1 (PPT1). Currently there is no effective treatment for children with INCL. In this study, newborn PPT1-deficient mice received two (cortex), four (cortex and hippocampus), or six (cortex, hippocampus, and cerebellum) bilateral intracranial injections of AAV2-PPT1. The AAV-treated animals had localized increases in PPT1 activity, decreased autofluorescent material, improved histologic parameters, and increased brain mass. In addition, the treated animals had dose-dependent improvements in a battery of behavioral tests and improved interictal electroencephalographic tracings. However, there was neither a significant decrease in seizure frequency nor an increase in longevity even in INCL animals receiving six injections. These data suggest that early treatment of INCL using gene transfer techniques can be efficacious. However, higher levels or a broader distribution of PPT1 expression, or both, will be required for more complete correction of this neurodegenerative disease.
Griffey
Megan A
MA
Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Wozniak
David
D
Wong
Michael
M
Bible
Ellen
E
Johnson
Kendra
K
Rothman
Steven M
SM
Wentz
Annie E
AE
Cooper
Jonathan D
JD
Sands
Mark S
MS
D000818:Animals; D001921:Brain / Q000378:metabolism / Q000502:physiology* / Q000821:virology; D002648:Child; D002675:Child, Preschool; D000229:Dependovirus / Q000235:genetics* / Q000502:physiology; D004195:Disease Models, Animal; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000502:physiology / Q000627:therapeutic use*; D006801:Humans; D008136:Longevity; D008565:Membrane Proteins / Q000008:administration & dosage / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009472:Neuronal Ceroid-Lipofuscinoses / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology* / Q000628:therapy*; D013869:Thiolester Hydrolases / Q000172:deficiency / Q000235:genetics
D008565:Membrane Proteins; D013869:Thiolester Hydrolases; C416054:PPT1 protein, human; C095299:palmitoyl-protein thioesterase