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Long-term effect of gene therapy on Leber’s congenital amaurosis.

Bainbridge, J.W.B. and Sundaram, V. and Mehat, M.S. and Robbie, S.R. and Barker, S.E. and Ripamonti, C. and Georgiadis, A. and Mowat, F.M. and Gardner, P.J. and Feathers, K.L. and Luong, V.A. and Beattie, S.G. and Yzer, S. and Balaggan, K. and Viswanathan, A. and de Ravel, T.J.L. and Casteels, I. and Holder, G. and Tyler, N. and Fitzke, F and Weleber, R.G. and Nardini, M. and Moore, A. and Thompson, D.A. and Petersen-Jones, S.M. and Michaelides, M. and van den Born, L.I. and Stockman, A. and Smith, A.J. and Rubin, G. and Ali, R.R. (2015) 'Long-term effect of gene therapy on Leber’s congenital amaurosis.', The New England journal of medicine., 372 (20). pp. 1887-1897.


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.)

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Publisher 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, S.G. Beattie, P.J. Gardner, K.L. Feathers, V.A. Luong, S. Yzer, K. Balaggan, A. Viswanathan, T.J.L. de Ravel, I. Casteels, G.E. Holder, N. Tyler, F.W. Fitzke, R.G. Weleber, M. Nardini, A.T. Moore, D.A. Thompson, 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.
Date accepted:13 March 2015
Date deposited:18 November 2015
Date of first online publication:May 2015
Date first made open access:No date available

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