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Durham University



Publication details for Professor Marko Nardini

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. (2015). Long-Term Effect of Gene Therapy on Leber’s Congenital Amaurosis. The New England Journal of Medicine 372(20): 1887-1897.

Author(s) from Durham


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.
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.
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.
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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