In gene therapy for RP and LCA, the sooner the better

It is the only approved ocular gene therapy and targets two forms of specific genetic mutations. hereditary retinal diseaseA real-world study in the UK has shown evidence that young children who undergo this procedure have significantly better vision than adults.

The study included 14 eyes of eight patients with two types of inherited retinal diseases caused by biallelic mutations. RPE65 Gene — retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA) — patients treated with gene therapy. Voletigene Nepalbovek (Luxturna). The researchers found that visual acuity improved by an average of 1.8 lines, along with improvements in functional tests such as contrast sensitivity, said Asad Jalil MBBS, lead clinician in vitreoretinal surgery at Manchester Royal Eye Hospital in Manchester, UK. He reported on September 20th. Euretina 2024 In Barcelona.

The FDA approved voretigene neparvovec in 2017, and the European Union also approved the treatment the following year.

“These are early results, but there's a consistent theme across all of the studies that have actually been published that the earlier the treatment, the better,” Jalil said. Medscape Medical News. “If we treat the child early, before the photoreceptors undergo irreversible damage, we may actually preserve more photoreceptor function.”

Jalil said in his presentation that the full-field stimulation test (FST), which measures rod-mediated photoreceptor function, improved in all patients evaluated. The study population included two adults and six children who underwent gene transfer surgery in both eyes, four of whom underwent gene transfer surgery in both eyes.

Two young patients (ages 13 and 17) who had surgery on both eyes had an average improvement of 4.15 log units (equivalent to 41.5 dB) on the FST test, Jalil said. Adult patients (30 and 40 years) who had surgery on both eyes had a mean improvement in FST of 0.45 log units. Although four of the younger patients (4 to 7 years old) were too young to undergo FST, Dr. Jalil said, “It is very difficult to perform FST on children because the test taker needs to respond to visual stimuli.'' “It's difficult,” he explained.

Low-light visual acuity, which measures how well you see in dark conditions, improved in the younger patients but not in the two adults, Jalil said.

Major retinal surgery in children

Treatment with voretigene neparvovec involves extensive vitreoretinal surgery, which creates a blister or bubble under the retina and places the gene vector inside.

“People may think they should wait to have surgery in children, but this is a lifelong disease,” Jalil said. medscape. “However, once photoreceptors are irreversibly damaged, it is difficult to restore visual function. The key is to immediately test a patient with inherited retinal dystrophy, retinitis pigmentosa, or Leber's disease for genetic testing. and check if it mutates RPE165we provide treatment at a very early stage. ”

Among the study population, three eyes had vitritis one month after surgery, which resolved with no sequelae, Jalil said. in one eye anterior uveitistwo had macular edema and loss of ellipsoidal area. Two years after surgery, one patient had progressive peripapillary atrophy and decreased visual acuity in both eyes.

Although younger patients in this population fared better than adults, this finding does not exclude the possibility of voletigen neparvovec for adults with biallelic RP or LCA, Jalil said. RPE65 mutation.

“For adults, the problem is that there are no other treatments, so it may be somewhat effective,” he says. “Their eyesight is already pretty bad and their field of vision is pretty impaired, so when we did this FST we found that their sensitivity to light improved somewhat and subjectively they were able to see a little bit better in the dark. I am saying.”

But he urged caution when treating adults. “You have to manage the expectation that you might see better in the dark, but if you already have irreversible damage to your photoreceptors and retina, you're not going to expect much improvement.”

Is the fovea detached?

In his presentation, Jalil acknowledged that there is an ongoing debate among retinal surgeons about whether the fovea should be detached during the vector placement procedure.

“The jury is still out, but this is what the clinical trials say, and this is what the original Luxturna manual still says.” [that] “When you inject it, you should separate the fovea,” he said. Since the problem is with the rods and perifoveal photoreceptors, foveal detachment can be avoided if current vision is fairly good. ”

In cases of poor vision, he said, his group separates the fovea and creates a blister, with a caveat. “Effectively, what we are aiming for is a region that is not ectopic around the supratemporal arcade, as confirmed by optical coherence tomography,” he added.

Jalil disclosed financial relationships with Alcon, DORC and Novartis.

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