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Long-Term Effect of Gene Therapy on Leber’s Congenital Amaurosis

Bainbridge, J.W.B.; Sundaram, V.; Mehat, M.S.; Robbie, S.R.; Barker, S.E.; Ripamonti, C.; Georgiadis, A.; Mowat, F.M.; Gardner, P.J.; Feathers, K.L.; Luong, V.A.; Beattie, S.G.; Yzer, S.; Balaggan, K.; Viswanathan, A.; de Ravel, T.J.L.; Casteels, I.; Holder, G.; Tyler, N.; Fitzke, F; Weleber, R.G.; Nardini, M.; Moore, A.; Thompson, D.A.; Petersen-Jones, S.M.; Michaelides, M.; van den Born, L.I.; Stockman, A.; Smith, A.J.; Rubin, G.; Ali, R.R.

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J.W.B. Bainbridge

V. Sundaram

M.S. Mehat

S.R. Robbie

S.E. Barker

C. Ripamonti

A. Georgiadis

F.M. Mowat

P.J. Gardner

K.L. Feathers

V.A. Luong

S.G. Beattie

S. Yzer

K. Balaggan

A. Viswanathan

T.J.L. de Ravel

I. Casteels

G. Holder

N. Tyler

F Fitzke

R.G. Weleber

A. Moore

D.A. Thompson

S.M. Petersen-Jones

M. Michaelides

L.I. van den Born

A. Stockman

A.J. Smith

G. Rubin

R.R. Ali


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; number, NCT00643747.)


Bainbridge, J., Sundaram, V., Mehat, M., Robbie, S., Barker, S., Ripamonti, C., …Ali, R. (2015). Long-Term Effect of Gene Therapy on Leber’s Congenital Amaurosis. New England Journal of Medicine, 372(20), 1887-1897.

Journal Article Type Article
Acceptance Date Mar 13, 2015
Publication Date May 14, 2015
Deposit Date May 5, 2015
Publicly Available Date Nov 18, 2015
Journal New England Journal of Medicine
Print ISSN 0028-4793
Electronic ISSN 1533-4406
Publisher Massachusetts Medical Society
Peer Reviewed Peer Reviewed
Volume 372
Issue 20
Pages 1887-1897


Published Journal Article (679 Kb)

Copyright Statement
From The New England Journal of Medicine, J.W.B. Bainbridge, M.S. Mehat, V. Sundaram, S.J. Robbie, S.E. Barker, C. Ripamonti, A. Georgiadis, F.M. Mowat,<br /> S.G. Beattie, P.J. Gardner, K.L. Feathers, V.A. Luong, S. Yzer, K. Balaggan, A. Viswanathan, T.J.L. de Ravel,<br /> I. Casteels, G.E. Holder, N. Tyler, F.W. Fitzke, R.G. Weleber, M. Nardini, A.T. Moore, D.A. Thompson,<br /> S.M. Petersen‑Jones, M. Michaelides, L.I. van den Born, A. Stockman, A.J. Smith, G. Rubin, and R.R. Ali, Long-Term Effect of Gene Therapy on Leber’s Congenital Amaurosis, 372, 1887-1897 Copyright © 2015 Massachusetts Medical Society. Reprinted with permission.

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