TY - JOUR
T1 - Adeno-associated virus 2-mediated gene therapy decreases autofluorescent storage material and increases brain mass in a murine model of infantile neuronal ceroid lipofuscinosis
AU - Griffey, Megan
AU - Bible, Ellen
AU - Vogler, Carole
AU - Levy, Beth
AU - Gupta, Praveena
AU - Cooper, Jonathan
AU - Sands, Mark S.
N1 - Funding Information:
We would like to thank Stephen Shemilt for his expert advice, members of the PSDL for their valuable contributions, and Drs. M. Lim and A. Barnwell for constructive comments on the manuscript. Special thanks to Annie Wentz for excellent technical support. These studies were supported in part by National Institutes of Health grants NS043205 (MSS) and NS41930 (JDC) and a grant from the Genzyme corporation (MSS). The following nonprofit agencies also contributed financially to this work: The Batten Disease Support and Research Association (MSS and EB), the Sam and Joey Fund (MSS), the Neuronal Ceroid Lipofuscinosis Research Alliance (MSS), and the Children's Brain Disease Foundation (MSS).
PY - 2004/7
Y1 - 2004/7
N2 - Infantile neuronal ceroid lipofuscinosis (INCL) is the earliest onset form of a class of inherited neurodegenerative disease called Batten disease. INCL is caused by a deficiency in the lysosomal enzyme palmitoyl protein thioesterase-1 (PPT1). Autofluorescent storage material accumulates in virtually all tissues in INCL patients, including the brain, and leads to widespread neuronal loss and cortical atrophy. To determine the efficacy of viral-mediated gene therapy, we injected a recombinant adeno-associated virus 2 vector encoding human PPT1 (rAAV-PPT1) intracranially (I.C.) into a murine model of INCL. INCL mice given four I.C. injections of rAAV-PPT1 as newborns exhibited PPT1 activity near the injection sites and decreased secondary elevations of another lysosomal enzyme. In addition, storage material was decreased in cortical, hippocampal, and cerebellar neurons, and brain weights and cortical thicknesses were increased. These data demonstrate that an adeno-associated virus 2 (AAV2)-mediated gene therapy approach may provide some therapeutic benefit for INCL.
AB - Infantile neuronal ceroid lipofuscinosis (INCL) is the earliest onset form of a class of inherited neurodegenerative disease called Batten disease. INCL is caused by a deficiency in the lysosomal enzyme palmitoyl protein thioesterase-1 (PPT1). Autofluorescent storage material accumulates in virtually all tissues in INCL patients, including the brain, and leads to widespread neuronal loss and cortical atrophy. To determine the efficacy of viral-mediated gene therapy, we injected a recombinant adeno-associated virus 2 vector encoding human PPT1 (rAAV-PPT1) intracranially (I.C.) into a murine model of INCL. INCL mice given four I.C. injections of rAAV-PPT1 as newborns exhibited PPT1 activity near the injection sites and decreased secondary elevations of another lysosomal enzyme. In addition, storage material was decreased in cortical, hippocampal, and cerebellar neurons, and brain weights and cortical thicknesses were increased. These data demonstrate that an adeno-associated virus 2 (AAV2)-mediated gene therapy approach may provide some therapeutic benefit for INCL.
KW - Adeno-associated virus
KW - Batten disease
KW - Gene therapy
KW - Infantile neuronal ceroid lipofuscinosis
KW - Lysosomal storage disease
KW - Neurodegenerative disease
KW - Palmitoyl protein thioesterase
UR - http://www.scopus.com/inward/record.url?scp=2942588715&partnerID=8YFLogxK
U2 - 10.1016/j.nbd.2004.03.005
DO - 10.1016/j.nbd.2004.03.005
M3 - Article
C2 - 15193292
AN - SCOPUS:2942588715
SN - 0969-9961
VL - 16
SP - 360
EP - 369
JO - Neurobiology of Disease
JF - Neurobiology of Disease
IS - 2
ER -