PMID- 15979943
OWN - NLM
STAT- MEDLINE
DCOM- 20051123
LR  - 20121115
IS  - 1525-0016 (Print)
IS  - 1525-0016 (Linking)
VI  - 12
IP  - 3
DP  - 2005 Sep
TI  - AAV2-mediated ocular gene therapy for infantile neuronal ceroid lipofuscinosis.
PG  - 413-21
AB  - Infantile neuronal ceroid lipofuscinosis (INCL) is a neurodegenerative disorder 
      caused by mutations in the gene encoding the lysosomal enzyme palmitoyl protein 
      thioesterase-1 (PPT1). The earliest clinical sign in INCL is blindness, followed 
      by seizures, cognitive deficits, and early death. Little is known about the 
      progression of the visual deficits in INCL. Here we characterize the progressive 
      retinal dysfunction and examine the efficacy of AAV2-mediated ocular gene therapy 
      in the murine model of INCL. Significant decreases in both mixed rod/cone and 
      pure cone electroretinographic amplitudes were observed at as early as 2 months 
      of age. Intravitreal injection of AAV2-PPT1 increased enzyme levels in the eye to 
      greater than normal levels. The increased PPT1 activity correlated with 
      improvements in the histological abnormalities as well as both mixed rod/cone and 
      pure cone functions. We also demonstrated that palmitoyl protein thioesterase-1 
      activity was detected in the brain following intravitreal injection. The brain 
      activity is likely due to anterograde axonal transport along the optic tracts. 
      Interestingly, the degree of neurodegeneration throughout the visual pathways of 
      the brain was greatly reduced in AAV-treated INCL mice. Therefore, intravitreal 
      AAV-mediated gene therapy has direct benefits to the eye and to distal sites in 
      the brain along the visual pathways.
FAU - Griffey, Megan
AU  - Griffey M
AD  - Department of Internal Medicine, Washington University School of Medicine, 660 
      South Euclid Avenue, St. Louis, MO 63110, USA.
FAU - Macauley, Shannon L
AU  - Macauley SL
FAU - Ogilvie, Judith M
AU  - Ogilvie JM
FAU - Sands, Mark S
AU  - Sands MS
LA  - eng
GR  - DC04665/DC/NIDCD NIH HHS/United States
GR  - DK57586/DK/NIDDK NIH HHS/United States
GR  - EY02687/EY/NEI NIH HHS/United States
GR  - NS43205/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Mol Ther
JT  - Molecular therapy : the journal of the American Society of Gene Therapy
JID - 100890581
RN  - 0 (DNA, Complementary)
RN  - EC 3.1.2.- (Thiolester Hydrolases)
RN  - EC 3.1.2.22 (palmitoyl-protein thioesterase)
SB  - IM
MH  - Animals
MH  - Axons/metabolism
MH  - Brain/metabolism
MH  - DNA, Complementary/metabolism
MH  - Dependovirus/*genetics
MH  - Disease Models, Animal
MH  - Electroretinography
MH  - Genetic Therapy/*methods
MH  - Genetic Vectors
MH  - Immunohistochemistry
MH  - Lysosomes/enzymology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mutation
MH  - Neuronal Ceroid-Lipofuscinoses/genetics/*therapy
MH  - Neurons/metabolism
MH  - Polymerase Chain Reaction
MH  - Retina/metabolism/pathology
MH  - Thiolester Hydrolases/*genetics
MH  - Time Factors
EDAT- 2005/06/28 09:00
MHDA- 2005/12/13 09:00
CRDT- 2005/06/28 09:00
PHST- 2004/12/10 00:00 [received]
PHST- 2005/03/24 00:00 [revised]
PHST- 2005/04/04 00:00 [accepted]
PHST- 2005/06/28 09:00 [pubmed]
PHST- 2005/12/13 09:00 [medline]
PHST- 2005/06/28 09:00 [entrez]
AID - S1525-0016(05)00191-7 [pii]
AID - 10.1016/j.ymthe.2005.04.018 [doi]
PST - ppublish
SO  - Mol Ther. 2005 Sep;12(3):413-21. doi: 10.1016/j.ymthe.2005.04.018.