UCL Discovery
UCL home » Library Services » Electronic resources » UCL Discovery

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

Bainbridge, JWB; Mehat, MS; Sundaram, V; Robbie, SJ; Barker, SE; Ripamonti, C; Georgiadis, A; ... Ali, RR; + view all (2015) Long-Term Effect of Gene Therapy on Leber's Congenital Amaurosis. New England Journal of Medicine , 372 (20) pp. 1887-1897. 10.1056/NEJMoa1414221. Green open access

[img]
Preview
Text
Bainbridge_VoR_long_term_effect_of_gene_therapy.pdf

Download (636kB) | Preview

Abstract

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.)

Type: Article
Title: Long-Term Effect of Gene Therapy on Leber's Congenital Amaurosis
Open access status: An open access version is available from UCL Discovery
DOI: 10.1056/NEJMoa1414221
Publisher version: http://dx.doi.org/10.1056/NEJMoa1414221
Language: English
Additional information: This version is the version of record. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Rpe65 Mutations, Adenoassociated Virus, Subretinal Injection, Retinal-detachment, Expressing Rpe65, Blindness, Vision, Muller, Cells, Degeneration
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology
UCL > Provost and Vice Provost Offices > UCL BEAMS
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science > Dept of Civil, Environ and Geomatic Eng
URI: https://discovery.ucl.ac.uk/id/eprint/1477968
Downloads since deposit
121Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item