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  • VN Gene Therapy for Inherited Retinal Dystrophy Linked to RPE65 Mutation

    By Lynda Seminara
    Selected By: Stephen D. McLeod, MD

    Journal Highlights

    Ophthalmology, September 2019

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    Maguire et al. looked at the efficacy, durability, and safety of voretigene neparvovec-rzyl (VN) adeno-associated viral vector–based gene therapy for in­herited retinal dystrophy (IRD) caused by RPE65 mutation. They reported findings of a phase 1 follow-on study (year 4) and a phase 3 open-label, ran­domized controlled trial (year 2), which suggest that the treatment effect lasts at least four years. The safety profile in their study was consistent with that of vitrectomy and subretinal injection procedures; no deleterious immune responses occurred.

    This investigation included 40 patients who received 1.5 × 1011 vector genomes of VN in at least one eye (phase 1, n = 11; phase 3, n = 29 [20 with original intervention, nine with control/intervention]). The investiga­tors documented outcomes of subreti­nal VN injection into the second eye of phase 1 subjects and into both eyes of phase 3 subjects.

    Endpoints common to both studies included full-field light sensitivity threshold (FST) testing and changes in performance on the multiluminance mobil­ity test (MLMT) within the illuminance range evaluated. Safety was assessed by adverse-event reporting, lab results, and findings of ophthalmic and physical examinations.

    For phase 1 subjects, the mean change in MLMT lux score was 2.4 at four years posttreatment versus 2.6 at year 1. Among phase 3 participants, the mean score change was 1.9 at year 2 versus 1.9 at year 1 in original inter­vention subjects, and 2.1 at one year among control/intervention subjects. In general, all three groups main­tained improvement in FST, denoting light-sensitivity improvement of more than 2 log10 (cd.s/m2) at year 1 and at subsequent follow-up visits for participating patients. The safety profile resembled that of vitrectomy and the subretinal injection procedure. There were no adverse immune responses.

    VN was approved by the FDA in 2017 and represents the first authorized pharmacologic treatment for this type of IRD. The pooled results from these studies demonstrate the favorable bene­fit-risk profile of this gene therapy.

    Observation is ongoing and will provide greater insight into the longer-term efficacy and safety profiles. In the interim, the authors emphasized the need for accurate diagnosis of IRD by genetic testing to identify the patients most likely to benefit from this treat­ment and other types of gene therapy. (See also related commentary by Stephen H. Tsang, MD, PhD, in the same issue.)

    The original article can be found here.