TY - JOUR
T1 - CNS-directed AAV2-mediated gene therapy ameliorates functional deficits in a murine model of infantile neuronal ceroid lipofuscinosis
AU - Griffey, Megan A.
AU - Wozniak, David
AU - Wong, Michael
AU - Bible, Ellen
AU - Johnson, Kendra
AU - Rothman, Steven M.
AU - Wentz, Annie E.
AU - Cooper, Jonathan D.
AU - Sands, Mark S.
N1 - Funding Information:
This work was supported in part by Grants NS043205 (M.S.S.) and NS41930 (J.D.C.) from the National Institutes of Health. The following nonprofit organizations also contributed financially to this work: the Batten Disease Support and Research Association (M.S.S. and E.B.), the Natalie Fund (J.D.C.), the Batten Disease Family Association (J.D.C.), and the Remy Fund (J.D.C.).
PY - 2006/3
Y1 - 2006/3
N2 - 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 (≈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.
AB - 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 (≈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.
UR - http://www.scopus.com/inward/record.url?scp=32944454332&partnerID=8YFLogxK
U2 - 10.1016/j.ymthe.2005.11.008
DO - 10.1016/j.ymthe.2005.11.008
M3 - Article
C2 - 16364693
AN - SCOPUS:32944454332
SN - 1525-0016
VL - 13
SP - 538
EP - 547
JO - Molecular Therapy
JF - Molecular Therapy
IS - 3
ER -