Long-term effect of gene therapy on Leber’s congenital amaurosis
Reviewed by Jonathan C P Roos

After reporting the first successful gene therapy results for RPE65 deficiency in three patients in a brief report in 2008, the same team from London now report the results of 12 patients followed up for three years after transfection. As part of a phase 1-2 open label trial, four patients were given a lower dose of adeno-associated virus vector carrying RPE65, whilst eight were given a higher dose. Unfortunately, only six patients showed some improvement in retinal sensitivity but the effect was not long-lasting and after a peak at around a year or so post transfection, there was a decline. ERG did not detect improvement in retinal function. Two patients had a significant deterioration in vision and three developed uveitis. These results could therefore be seen as disappointing after the early promise. However, this trial provides some valuable lessons. First, those with higher dose transfection were more likely to have an improvement, and second, an improvement is possible but may require repeat treatment for a sustained effect. In order to investigate the dose-response relationship between vector and retinal improvement the same group performed a parallel study in Briard dogs which carry an RPE65 mutation. The team found that improvements measurable by ERG could be achieved, but that this was dose dependent. The implication of course is that there is a different amount of RPE65 required in different species to maintain the visual cycle and if better promoters can be developed which increase expression there is hope that this can become a successful therapy in the future.

Long-term effect of gene therapy on Leber’s congenital amaurosis.
Bainbridge JW, Mehat M, Sundaram S, et al.
NEW ENGLAND JOURNAL OF MEDICINE
2015;372:1887-97.