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

摘要

BACKGROUNDudMutations in RPE65 cause Leber’s congenital amaurosis, a progressive retinal degenerativeuddisease that severely impairs sight in children. Gene therapy can resultudin modest improvements in night vision, but knowledge of its efficacy in humansudis limited.udMETHODSudWe performed a phase 1–2 open-label trial involving 12 participants to evaluate theudsafety and efficacy of gene therapy with a recombinant adeno-associated virus 2/2ud(rAAV2/2) vector carrying the RPE65 complementary DNA, and measured visualudfunction over the course of 3 years. Four participants were administered a loweruddose of the vector, and 8 were administered a higher dose. In a parallel study inuddogs, we investigated the relationship among vector dose, visual function, andudelectroretinography (ERG) findings.udRESULTSudImprovements in retinal sensitivity were evident, to varying extents, in six participantsudfor up to 3 years, peaking at 6 to 12 months after treatment and then declining.udNo associated improvement in retinal function was detected by means of ERG.udThree participants had intraocular inflammation, and two had clinically significantuddeterioration of visual acuity. The reduction in central retinal thickness variedudamong participants. In dogs, RPE65 gene therapy with the same vector at loweruddoses improved vision-guided behavior, but only higher doses resulted in improvementsudin retinal function that were detectable with the use of ERG.udCONCLUSIONSudGene therapy with rAAV2/2 RPE65 vector improved retinal sensitivity, albeit modestlyudand temporarily. Comparison with the results obtained in the dog modeludindicates that there is a species difference in the amount of RPE65 required touddrive the visual cycle and that the demand for RPE65 in affected persons was notudmet to the extent required for a durable, robust effect. (Funded by the NationaludInstitute for Health Research and others; ClinicalTrials.gov number, NCT00643747.)