PMID- 18463687
OWN - NLM
STAT- MEDLINE
DCOM- 20081204
LR  - 20211103
IS  - 1476-5462 (Electronic)
IS  - 0969-7128 (Print)
IS  - 0969-7128 (Linking)
VI  - 15
IP  - 19
DP  - 2008 Oct
TI  - Correction of the disease phenotype in the mouse model of Stargardt disease by 
      lentiviral gene therapy.
PG  - 1311-20
LID - 10.1038/gt.2008.78 [doi]
AB  - Autosomal recessive Stargardt disease (STGD1) is a macular dystrophy caused by 
      mutations in the ABCA4 (ABCR) gene. The disease phenotype that is most recognized 
      in STGD1 patients, and also in the Abca4-/- mouse (a disease model), is 
      lipofuscin accumulation in retinal pigment epithelium. Here, we tested whether 
      delivery of the normal (wt) human ABCA4 gene to the subretinal space of the Abca4 
      -/- mice via lentiviral vectors would correct the disease phenotype; that is, 
      reduce accumulation of the lipofuscin pigment A2E. Equine infectious anemia virus 
      (EIAV)-derived lentiviral vectors were constructed expressing either the human 
      ABCA4 gene or the LacZ reporter gene under the control of the constitutive (CMV) 
      or photoreceptor-specific (Rho) promoters. Abca4-/- mice were injected 
      subretinally with 1 microl ( approximately 5.0 x 10(5) TU) of each EIAV vector in 
      one eye at postnatal days 4 and 5. An injection of saline, an EIAV-null vector, 
      or an uninjected contralateral eye served as a control. Mice were killed at 
      various times after injection to determine photoreceptor (PR) transduction 
      efficiency and A2E concentrations. EIAV-LacZ vectors transduced from 5 to 20% of 
      the PRs in the injected area in mice. Most importantly, a single subretinal 
      injection of EIAV-CMV-ABCA4 to Abca4-/- mouse eyes substantially reduced 
      disease-associated A2E accumulation compared to untreated and mock-treated 
      control eyes. Treated eyes of Abca4-/- mice accumulated 8-12 pmol per eye 
      (s.d.=2.7) of A2E 1 year after treatment, amounts comparable to wt controls, 
      whereas mock-treated or untreated eyes had 3-5 times more A2E (27-39 pmol per 
      eye, s.d.=1.5; P=0.001-0.005). Although extrapolation to humans requires caution, 
      the high transduction efficiency of both rod and cone photoreceptors and the 
      statistically significant reduction of A2E accumulation in the mouse model of 
      STGD1 suggest that lentiviral gene therapy is a potentially efficient tool for 
      treating ABCA4-associated diseases.
FAU - Kong, J
AU  - Kong J
AD  - Department of Ophthalmology, Columbia University, New York, NY 10032, USA.
FAU - Kim, S-R
AU  - Kim SR
FAU - Binley, K
AU  - Binley K
FAU - Pata, I
AU  - Pata I
FAU - Doi, K
AU  - Doi K
FAU - Mannik, J
AU  - Mannik J
FAU - Zernant-Rajang, J
AU  - Zernant-Rajang J
FAU - Kan, O
AU  - Kan O
FAU - Iqball, S
AU  - Iqball S
FAU - Naylor, S
AU  - Naylor S
FAU - Sparrow, J R
AU  - Sparrow JR
FAU - Gouras, P
AU  - Gouras P
FAU - Allikmets, R
AU  - Allikmets R
LA  - eng
GR  - R01 EY013435/EY/NEI NIH HHS/United States
GR  - R01 EY012951/EY/NEI NIH HHS/United States
GR  - R01 EY012951-11/EY/NEI NIH HHS/United States
GR  - EY12951/EY/NEI NIH HHS/United States
GR  - EY13435/EY/NEI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20080508
PL  - England
TA  - Gene Ther
JT  - Gene therapy
JID - 9421525
RN  - 0 (ABCA4 protein, human)
RN  - 0 (ATP-Binding Cassette Transporters)
SB  - IM
MH  - ATP-Binding Cassette Transporters/analysis/*genetics
MH  - Animals
MH  - Corneal Dystrophies, Hereditary/metabolism/*therapy
MH  - Electroretinography
MH  - Genetic Engineering
MH  - Genetic Therapy/*methods
MH  - Genetic Vectors/*administration & dosage/genetics
MH  - Homozygote
MH  - Humans
MH  - Immunohistochemistry
MH  - Lentivirus/*genetics
MH  - Mice
MH  - Mice, Knockout
MH  - Phenotype
MH  - Retina/chemistry/metabolism
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Transduction, Genetic/*methods
MH  - Transgenes
PMC - PMC3110063
MID - NIHMS284368
EDAT- 2008/05/09 09:00
MHDA- 2008/12/17 09:00
PMCR- 2011/06/07
CRDT- 2008/05/09 09:00
PHST- 2008/05/09 09:00 [pubmed]
PHST- 2008/12/17 09:00 [medline]
PHST- 2008/05/09 09:00 [entrez]
PHST- 2011/06/07 00:00 [pmc-release]
AID - gt200878 [pii]
AID - 10.1038/gt.2008.78 [doi]
PST - ppublish
SO  - Gene Ther. 2008 Oct;15(19):1311-20. doi: 10.1038/gt.2008.78. Epub 2008 May 8.