In Gene Therapy for RP, LCA, the Earlier, the Better

The only approved ocular gene therapy, which targets a specific gene mutation in two forms of inherited retinal disease, has shown evidence in a real-world study from the United Kingdom that young children derive a greater improvement in vision than adults who undergo the procedure. 

The study included 14 eyes in eight patients with two types of inherited retinal disease caused by mutations of the biallelic RPE65 gene — retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA) — who were treated with the gene therapy voretigene neparvovec (Luxturna). The researchers found an average improvement in visual acuity of 1.8 lines, along with improvements in functional tests such as contrast sensitivity, Assad Jalil, MBBS, lead clinician of vitreoretinal surgery at Manchester Royal Eye Hospital, Manchester, United Kingdom, reported on September 20 at EURETINA 2024 in Barcelona. 

The FDA approved voretigene neparvovec in 2017, with the European Union approving the therapy the following year.

“These are initial results, but there is a consistent theme with all the studies that have come out practically that the earlier you do the treatment, the better,” Jalil told Medscape Medical News. “If you do the treatment early in children, before the photoreceptors are irreversibly damaged, they would actually preserve their function more.”

In his presentation, Jalil said full-field stimulus testing (FST), which measures rod-mediated function of the photoreceptors, improved in all patients who had the assessments. The study population included two adults who had the gene-placement surgery in both eyes, and six children, four of whom had the procedure in both eyes. 

Two younger patients (aged 13 and 17 years) who had the procedure in both eyes had an average improvement in FST testing of 4.15 log units, equal to 41.5 dB, Jalil said. The adult patients (aged 30 and 40 years) who had the procedure in both eyes had an average improvement on FST of 0.45 log unit. Four of the younger patients (aged 4-7 years) were too young to undergo FST, which Jalil describe is “very difficult to do in children” because it requires the individual undergoing testing to respond to visual stimuli. 

Low-luminance visual acuity, which indicates vision in low-light situations, improved in the younger patients but not in the two adults, Jalil said.

Major Retinal Surgery in Children

Treatment with voretigene neparvovec involves major vitreoretinal surgery in which a bleb, or bubble, is created under the retina and the gene vector is placed within it. 

“People may think that with surgery in children, we should wait, and this is a lifelong disease,” Jalil told Medscape. “But once the photoreceptors are irreversibly damaged, then it’s difficult to get the visual function back. The bottom line is, as soon as you see a patient with inherited retinal dystrophy, retinitis pigmentosa, or Leber’s, we do the genetic testing, and if it confirms the mutation of RPE165, we offer the treatment very early on.”

In the study population, three eyes had vitritis 1 month after surgery, which resolved without lingering effects, Jalil said. One eye had anterior uveitis, and two had macular edema and ellipsoid zone loss. Two years after surgery, one patient had increased peripapillary atrophy with decreased vision in both eyes. 

Although younger patients in this population fared better than adults, Jalil said this finding does not obviate the potential of voretigene neparvovec for adults with RP or LCA due to biallelic RPE65 mutations.

“For adults, the problem is there is no other treatment, so there will be some benefit,” he said. “Their vision is already quite poor, their field of vision is already quite compromised, so we’ve done this FST and it has shown some improvement in light sensitivity, and subjectively they’ve said the see a bit more in the dark.”

However, he urged caution in treating adults: “You have to manage their expectations that they may see more in the dark, but there would not huge improvements if there is irreversible damage to the photoreceptors and the retina already.”

Fovea Detached or Not? 

In his presentation, Jalil acknowledged the ongoing debate among retinal surgeons regarding whether the fovea should be detached or not during the procedure to place the vector. 

“The jury is still out, but the clinical trials said and the original manual with Luxturna still says [that] when you inject it, you should detach the fovea,” he said. “However, if you’re doing it early on in children with good visual acuity, before there is loss of vision, you can argue that you’re trying to work on the rods and perifoveal photoreceptors, so that’s why we avoiding foveal detachment when the presenting visual acuity is pretty good.” 

In cases with poor vision, he said his group will detach the fovea to create the bleb — but with a caveat. “Effectively, what we go for is an area that’s not ectopic which is around the superotemporal arcade once you confirm it with optical coherence tomography,” he added.

Jalil disclosed financial relationships with Alcon, DORC, and Novartis. 

Richard Mark Kirkner is a medical journalist based in the Philadelphia area.