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Gene Therapy Offers Hope for Inherited Retinal Disorder

Gene Therapy Offers Hope for Inherited Retinal Disorder

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Action Points

  • Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.
  • Patients with inherited retinal disease due to biallelic mutation in the RPE65 gene had sustained functional vision improvement when treated with voretigene neparvovec (Luxturna), according to a phase III study in 29 patients.
  • Note that RPE65 is an isomerohydrolase enzyme (expressed in the retinal pigment epithelium) that converts vitamin A from an inactive to an active form, and is responsible for rod and cone functioning.

NEW ORLEANS — Gene augmentation by voretigene neparvovec (Luxturna) improves functional vision in patients with biallelic mutation in the RPE65 gene, a mutation that results in inherited retinal disease, researchers reported here.

Twenty seven of 29 (93%) of patients with Leber congenital amaurosis (LCA) who were treated with the investigational gene therapy had their vision improved to the degree that they could navigate a maze in low to moderate light. They also demonstrated improvement in light sensitivity and peripheral vision, according to Stephen R. Russell, MD, of the University of Iowa in Iowa City, and colleagues.

The improvement was maintained to 3 years, according to updated data from a phase III study presented at the American Academy of Ophthalmology (AAO) meeting.

In October, an FDA advisory committee unanimously recommended approval of the gene treatment for patients with vision loss due to confirmed biallelic RPEmutation-associated retinal dystrophy. The FDA is expected to render a decision no later than January 2018.

“So far, we have followed patients for up to 4 years, and have not seen any significant drop-off,” Russell said at an AAO, press briefing. “We will be observing these patients up to 15 years by FDA protocol.”

RPE65 is an isomerohydrolase enzyme expressed in the retinal pigment epithelium; this enzyme converts vitamin A from an inactive to an active form. The expression of the RPE65 gene is responsible for rod and cone functioning. Autosomal-recessive mutations in the RPE65 gene result in difficulty in navigating unfamiliar environments, night blindness, loss of visual acuity, and a progressive loss of the visual field.

The effect of noretigene neparvovec was studied in a 1-year open-label, randomized, controlled study period, after which patients in the control group could cross over to active treatment. The treatment was delivered bilaterally, 6 to 18 days apart.

The 31 patients, ages 4 to 44 years at the time of treatment, were randomized in a 2:1 ratio to treatment (n=21) or control (n=10).

The primary endpoint was the change in bilateral performance in the multi-luminance mobility test (MLMT), an endpoint designed specifically for LCA, at 1 year. The MLMT measures functional performance through navigation of a mobility course in which participants follow arrows and avoid obstacles. The test was conducted at various light levels, ranging from 1 to 400 lux. The course navigation was captured on video and graded for accuracy and time.

At 1 year, per the mean change in the bilateral MLMT score differed by 1.6 in favor of the active treatment (95% CI 0.72-2.41, P=0.0013). Those who received gene therapy also showed a marked improvement compared with controls in full-field light sensitivity (FST) threshold testing averaged over both eyes (P=0.0004) and MLMT change score for the first injected eye (P=0.0005).

However, the change in visual acuity averaged over both eyes was not significantly different between intervention and control patients (P=0.17).

The mean bilateral MLMT score change at 3 years for 20 patients originally randomized to gene augmentation was 1.8. In nine patients who crossed over, the mean bilateral score change was 2.1 relative to injection baseline after year 1.

Similarly, the mean change from baseline in white light FST was 2.04 at year 3 in 19 participants who received noretigene neparvovec. This same score improved by 2.69 at year 2 in the nine patients who crossed over.

The change in mean visual acuity score was consistent through year 2 for the crossover population and through year 3 in the population originally randomized to noretigene neparvovec. “We have a very small population, so there’s a lot of variability,” Russell stated.

“There were no serious ocular surgery concerns,” he said. “The complications that we saw were largely related to the procedure of placing the subretinal gene therapy as opposed to agent-related reactions.”

Ten patients (17%) had cataracts and three (10%) had intraoperative retinal tears that were treated at the time of gene therapy. Three patients (10%) had retinal deposits.

Irene Maumenee, MD, of the Ocular Genetics Laboratory at the University of Illinois in Chicago, said the results represent the beginning of a treatment wave of genetic eye disease, with further improvements down the road. She cautioned that it may be premature to treat without a full understanding of the variation in disease that occurs with mutation in the same gene.

“Has there ever been any treatment where the dosage was right from the beginning?” she stated. “Probably not. So if this is the first wave of treatment that would be 100% correct, [that ] is … maybe presumptuous. There are so many problems to overcome from the beginning.” Maumenee was not involved in the study.

Russell disclosed a relevant relationship with Spark Therapeutics.


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