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CRISPR-based gene editing improved vision without serious adverse effects in patients with CEP290-associated inherited retinal degeneration, an interim analysis of a small phase I/II study showed.

Among 14 patients who received the gene therapy known as EDIT-101, meaningful improvements from baseline occurred in best corrected visual acuity (four patients), cone-mediated vision (six patients), and vision-related quality-of-life scores (six patients), reported Mark Pennesi, MD, PhD, of Oregon Health & Science University in Portland, and colleagues.

Notably, no serious adverse events related to the treatment or procedure and no dose-limiting toxicities were observed, they wrote in the .

"Even though it didn't work in every patient, the fact that it worked in a number of patients is very exciting because it really shows the potential of this technology," Pennesi told 乌鸦传媒. "As ophthalmologists, we were often taught that there aren't really treatments for these rare genetic diseases. That is changing."

CEP290-associated inherited retinal degeneration is a devastating condition that affects one in 100,000 people, Pennesi said. It's often diagnosed in infancy and typically progresses to blindness.

The disease "is characterized by disorganized outer segments of rod and cone photoreceptors and early death of rods in the midperipheral retina, with the retention of cones in the macula (most central part of the retina)," the authors explained. There is no approved treatment for the condition.

EDIT-101 aims to improve vision via genes that are edited to remove a mutation. The goal is to repair non-working photoreceptor cells in the retina, Pennesi said. "This is not a cure because many of the patients already have cells that have been lost. We're not going to be able to bring back lost cells, but we can improve the function of the cells that are still there."

In the study, the mean change from baseline in best corrected visual acuity was -0.21 logMAR (90% CI -0.45 to 0.02) in the study eyes and -0.01 logMAR (90% CI -0.09 to 0.06) in the untreated contralateral (control) eyes. Four of 14 participants had improvement that reached the prespecified threshold for clinically meaningful improvement of at least 0.3 logMAR.

Of the six participants with a visually meaningful improvement in the study eye, the threshold in two patients improved by more than 1 log unit, which is close to the maximum possible cone-mediated improvement, and the threshold in four patients improved by month 3.

Vision-related quality-of-life scores improved by a mean 2.3 points (90% CI -3.9 to 8.6) from baseline on the National Eye Institute Visual Function Questionnaire-25 (for adults) or Children's Visual Function Questionnaire (for kids). The scores reached a level considered to be a meaningful improvement (at least 4 points higher than baseline) in six of 14 patients.

Pennesi said his institution has treated four patients. "They really noticed changes in vision," he said. One patient told him that she can now distinguish between food items on a plate, find a lost cell phone more easily, and detect her coffee machine's on-light.

The patient also started to watch television. "She used to just listen to TV, but now she can actually see some of the visual information," he said. "Little things like that are very meaningful to these patients."

The treatment is a one-time therapy, Pennesi explained, and the patients will probably be followed for the rest of their lives. It's not known if they'll continue to improve or if their vision will get worse.

In an interview, Ankur Sudhir Gupta, MD, of Stanford Byers Eye Institute in Palo Alto, California, said the study results are promising, although he cautioned that the use of gene editing via CRISPR in the retina is "uncharted territory."

Gupta, who was not involved in the study, added that the treatment is permanent and essentially reprograms genes. "You have to try to understand what the downstream consequences are," he said. However, he added, "the alternative is to do nothing."

For this open-label, single-ascending-dose study, patients ages 3 years and older with CEP290-associated inherited retinal degeneration caused by a homozygous or compound heterozygous IVS26 variant received a subretinal injection of EDIT-101 in the worse (study) eye.

The study included 12 adults (median age 37, 36% men) and two children ages 9 and 14 years (both boys). At baseline, the median best corrected visual acuity in the study eye was 2.4 log₁₀ of the minimum angle of resolution (range 3.9 to 0.6).

Adults received low, intermediate, or high doses of EDIT-101, while both kids received the intermediate dose. All patients received oral prednisone (0.5 mg/kg of body weight per day) for 3 days prior to treatment and for 4 weeks afterwards, followed by a 15-day taper.

At a median follow-up of 376 days, 22 ocular adverse events related to study treatment occurred in seven of 14 patients. None were considered serious or dose-limiting.

"There was one patient who [started] bleeding after the surgery," Pennesi said. "But that went away, and the vision recovered. That was really just a surgical issue that can happen anytime you do this kind of interactive surgery."

There was another patient "who showed development of reflective mounts in the retina, which we think could be inflammation," he added. "That's something we have seen before. We were able to treat them with steroids, and their vision improved."

As for the cost of EDIT-101 if approved in the future, Pennesi said it may be similar to the $425,000 cost of the FDA-approved gene therapy voretigene neparvovec (Luxturna), which treats biallelic RPE65-mediated inherited retinal disease. Insurers have been willing to cover that treatment, he noted.

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