MIXED RESULTS

Gene therapy targeting Leber’s congenital amaurosis LCA2 can improve rod function, retinal sensitivity and dark navigation. However, at three-year follow-up the magnitude of functional improvement was highly variable and the duration of maximum impact limited, apparently by progressive degeneration, James W Bainbridge MA, PhD, FRCOphth told the World Congress of Paediatric Ophthalmology and Strabismus in London. 
The results suggest that while the treatment does incorporate a gene into retinal pigment epithelium cells that expresses RPE65, which is needed for regenerating visual pigment in photoreceptor cells, the amount delivered using the current therapy is insufficient for sustained benefit. 
LCA2 results from a defect in a single gene that disrupts production of RPE65, leading to progressive loss of dark adaptation and outer retina degeneration. Since rod photoreceptors are entirely dependent on RPE65 for visual pigment recycling, infants with LCA2 have poor rod function from birth. 
Cones have an alternative regeneration source, so cone function is initially preserved, but is lost to progressive structural degeneration through the first three decades of life. Why degeneration occurs is unknown, though it may result from accumulation of retinyl esters due to interruption of the visual cycle, Dr Bainbridge said.
LCA2 is an attractive gene therapy target because it presents the possibility of restarting the visual cycle by supplying the normal gene, improving retinal function. Improved function also occurs quickly, making it a more practical endpoint than preventing degeneration, which may take years to demonstrate, Dr Bainbridge noted. 
In mouse and dog models, delivering the RPE65 gene using a recombinant adeno-associated virus vector improved retinal function markedly as measured by electroretinography, Dr Bainbridge said. When delivered early enough it also protected against structural degeneration.
Twelve patients participated in a Phase I/II open-label dose escalation trial. Each patient received a subretinal injection in their poorer-seeing eye of the human RPE65 gene controlled by an RPE65 promoter targeting retinal pigment epithelium cells. The rAAV2 vector was the same used in the animal models.
For safety reasons the first three patients were older, ranging in age from 17 to 23 years. Patients as young as six years were subsequently included. The first four patients received a dose of 1 x 1x1011 particles, with subsequent subjects receiving 1x1012, a 10-fold dose elevation.
“We were very pleased to see that even subjects with the lower dose and relatively advanced degeneration could benefit with improved retinal sensitivity on microperimetry,” Dr Bainbridge said. 
The response was also good among some younger children and at the higher dose. However, improvement was also highly variable. “We saw lower magnitude effect, or in some cases no discernible impact on microperimetry in some of the younger subjects in whom we might have expected a more robust response,” he added.
Patients also performed much better on dark-adapted perimetry with progressive improvement after as much as four hours. While this demonstrates efficacy, persistently delayed dark-adaptation suggests that the provision of RPE65 is suboptimal, Dr Bainbridge said. Durability of maximum impact was also limited. 
James Bainbridge: j.bainbridge@ucl.ac.uk
* See also: Page 48