Long-term effect of gene therapy on Leber's congenital amaurosis.
BACKGROUND
Mutations in RPE65 cause Leber's congenital amaurosis, a progressive retinal degenerative disease that severely impairs sight in children. Gene therapy can result in modest improvements in night vision, but knowledge of its efficacy in humans is limited.


METHODS
We performed a phase 1-2 open-label trial involving 12 participants to evaluate the safety and efficacy of gene therapy with a recombinant adeno-associated virus 2/2 (rAAV2/2) vector carrying the RPE65 complementary DNA, and measured visual function over the course of 3 years. Four participants were administered a lower dose of the vector, and 8 were administered a higher dose. In a parallel study in dogs, we investigated the relationship among vector dose, visual function, and electroretinography (ERG) findings.


RESULTS
Improvements in retinal sensitivity were evident, to varying extents, in six participants for up to 3 years, peaking at 6 to 12 months after treatment and then declining. No associated improvement in retinal function was detected by means of ERG. Three participants had intraocular inflammation, and two had clinically significant deterioration of visual acuity. The reduction in central retinal thickness varied among participants. In dogs, RPE65 gene therapy with the same vector at lower doses improved vision-guided behavior, but only higher doses resulted in improvements in retinal function that were detectable with the use of ERG.


CONCLUSIONS
Gene therapy with rAAV2/2 RPE65 vector improved retinal sensitivity, albeit modestly and temporarily. Comparison with the results obtained in the dog model indicates that there is a species difference in the amount of RPE65 required to drive the visual cycle and that the demand for RPE65 in affected persons was not met to the extent required for a durable, robust effect. (Funded by the National Institute for Health Research and others; ClinicalTrials.gov number, NCT00643747.).
From the UCL (University College London) Institute of Ophthalmology (J.W.B.B., M.S.M., V.S., S.J.R., S.E.B., C.R., A.G., F.M.M., S.G.B., P.J.G., V.A.L., K.B., A.V., G.E.H., F.W.F., M.N., A.T.M., M.M., A.S., A.J.S., G.R., R.R.A.) and the Department of Civil, Environmental, and Geomatic Engineering (N.T.), UCL, and Moorfields Eye Hospital (J.W.B.B., M.S.M., V.S., S.J.R., A.G., K.B., G.H., A.M., M.M.), London, and the Department of Psychology, Durham University, Durham (M.N.) - all in the United Kingdom; the College of Veterinary Medicine, Michigan State University, East Lansing (F.M.M., S.M.P.-J.), and the Kellogg Eye Center, University of Michigan Medical School, Ann Arbor (K.L.F., D.A.T., R.R.A.); the Center for Human Genetics, KU Leuven (T.J.L.R.), and the Department of Ophthalmology, UZ Leuven, Campus Sint-Rafaël (I.C.) - both in Leuven, Belgium; Rotterdam Eye Hospital, Rotterdam, the Netherlands (S.Y., L.I.B.); and the Oregon Retinal Degeneration Center, Ophthalmic Genetics Service, Casey Eye Institute, Oregon Health and Science University, Portland (R.G.W.).
James W B
JW
Bainbridge
Manjit S
MS
Mehat
Venki
V
Sundaram
Scott J
SJ
Robbie
Susie E
SE
Barker
Caterina
C
Ripamonti
Anastasios
A
Georgiadis
Freya M
FM
Mowat
Stuart G
SG
Beattie
Peter J
PJ
Gardner
Kecia L
KL
Feathers
Vy A
VA
Luong
Suzanne
S
Yzer
Kamaljit
K
Balaggan
Ananth
A
Viswanathan
Thomy J L
TJ
de Ravel
Ingele
I
Casteels
Graham E
GE
Holder
Nick
N
Tyler
Fred W
FW
Fitzke
Richard G
RG
Weleber
Marko
M
Nardini
Anthony T
AT
Moore
Debra A
DA
Thompson
Simon M
SM
Petersen-Jones
Michel
M
Michaelides
L Ingeborgh
LI
van den Born
Andrew
A
Stockman
Alexander J
AJ
Smith
Gary
G
Rubin
Robin R
RR
Ali
D000293:Adolescent; D000818:Animals; D002648:Child; D018076:DNA, Complementary / Q000008:administration & dosage*; D000229:Dependovirus; D004195:Disease Models, Animal; D018450:Disease Progression; D004285:Dogs; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage*; D006801:Humans; D057130:Leber Congenital Amaurosis / Q000235:genetics / Q000628:therapy*; D009154:Mutation; D020419:Photoreceptor Cells, Vertebrate; D012160:Retina / Q000502:physiology*; D014785:Vision, Ocular; D055815:Young Adult; D019745:cis-trans-Isomerases / Q000235:genetics*; D000099178:Retinoid Isomerohydrolase
D018076:DNA, Complementary; D019745:cis-trans-Isomerases; D000099178:Retinoid Isomerohydrolase