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    Investigators assessed 1-year safety and efficacy outcomes of voretigene neparvovec (AAV2-hRPE65v2), a gene replacement therapy for RPE65-mediated retinal dystrophies.

    Study design

    This randomized, controlled, open-label phase 3 trial included 29 participants with confirmed genetic diagnosis of biallelic RPE65 mutations. All subjects were at least 3 years of age, with BCVA of 20/60 or worse or visual field less than 20 degrees in any meridian. Twenty patients were randomized to receive a subretinal injection of voretigene neparvovec in the first eye, followed by a second injection of the same dose 6 to 18 days later. The remaining 9 subjects were assigned to observation without treatment (control).

    The primary efficacy endpoint was 1-year change in standardized bilateral multi-luminance mobility testing (MLMT)—a maze that assesses aspects of visual field, VA, light perception and contrast sensitivity—as scored by masked graders. A secondary efficacy endpoint was bilateral, full-field light sensitivity threshold (FST) testing, a measure of the physiological function of rod photoreceptors.


    After 1 year, there was a significantly higher mean bilateral MLMT change score for the treatment group than for the control group (1.8 vs. 0.2, P=0.0013). Patients’ response to the therapy was rapid; mean MLMT lux score improvement was observed at 30 days follow-up and remained stable throughout 1 year. Additionally, 13 (65%) of the treated participants passed the MLMT at the lowest tested luminance level (1 lux), demonstrating the maximum possible improvement in real-world function. In contrast, no subjects in the control group were able to pass the MLMT at 1 lux.

    Mean FST in the treatment group showed a greater than 2 log unit improvement in light sensitivity by day 30 that remained stable over 1 year, whereas the control group showed no meaningful change in this measure over the same period (P=0.0004). The most common ocular adverse events were transient mild ocular inflammation, transient elevated intraocular pressure and intraoperative retinal tears.


    This is a small study, as expected for such a rare disease. Extrapolating results is a challenge considering that MLMT is new and not widely used efficacy endpoint, but quantifying visual gains in studies such as this requires a novel, integrated approach beyond what is revealed by typical vision tests that are commonly used in clinics. A possible confounding factor is that baseline MLMT passing levels were not completely balanced between the treatment and control groups.

    Clinical Significance

    This is the first randomized, phase 3 gene therapy trial for a genetic disease. Bilateral vector administration led to meaningful and sustained improvements in the subjects’ ability to navigate independently in low-to-moderate light conditions. These findings indicate that the vector can successfully restore RPE65 enzymatic activity—crucial for light perception—in patients who would otherwise progress to blindness. The treatment effect may occur as early as 30 days after administration and is stable up to 1 year. Ongoing studies have suggested a treatment durability of at least 3 years.