A multinational study led by the LHON Study Group has revealed sustained visual improvements and a favorable safety profile five years following lenadogene nolparvovec gene therapy in patients with Leber hereditary optic neuropathy (LHON) caused by the MT-ND4 gene mutation.

LHON is most prevalently caused by the MT-ND4 gene mutation in mitochondrial DNA, characterized by acute and severe bilateral vision loss, primarily affecting retinal ganglion cells. Retinal ganglion cells are neurons tasked with relaying visual information from the retina to the brain

Lenadogene nolparvovec, an adeno-associated virus (AAV)-based gene therapy, was developed to address LHON and has been evaluated in four prior clinical studies, demonstrating early improvements.

The study, “Single-Eye Gene Therapy for Leber Hereditary Optic Neuropathy,” published in JAMA Ophthalmology, details the findings of RESTORE, a long-term follow-up of two earlier Phase III trials, RESCUE and REVERSE, assessing lenadogene nolparvovec’s efficacy for treating vision loss in LHON.

Participants involved in the RESCUE and REVERSE clinical trials received a single intravitreal injection in one eye, with the other eye receiving a sham injection. These earlier trials included patients with MT-ND4 mutation-associated LHON who experienced vision loss either within six months (RESCUE) or between six and 12 months (REVERSE) prior to treatment.

After two years in the initial trials, patients were enrolled in the RESTORE study for three additional years of monitoring. Of the 76 patients treated in the original trials, 72 completed the studies, and 62 were enrolled in RESTORE, with 55 completing the five-year follow-up.

Best-corrected visual acuity (BCVA) was measured using logMAR, and QoL assessments utilized the National Eye Institute Visual Functioning Questionnaire-25. Safety evaluations included monitoring for ocular and systemic adverse events.

Five years after treatment, participants demonstrated sustained bilateral improvements in BCVA. At baseline, the mean BCVA for treated eyes was 1.5 logMAR (20/600 Snellen), improving to 1.4 logMAR (20/500) at two years and remaining stable through year five.

The mean BCVA improvement from nadir (the worst recorded vision) was −0.4 logMAR (+4 lines on the Early Treatment Diabetic Retinopathy Study chart) in both treated and sham eyes.

Clinically relevant recovery, defined as a BCVA improvement of at least −0.3 logMAR (+3 lines), was observed in 66.1% of participants (41 of 62). Quality of life improved, with significant gains in seven of 10 NEI VFQ-25 subscales, including mental health and role difficulties, and a composite score increase of seven points.

Intriguingly, no significant differences were observed between treated and sham eyes. While in any other scenario, having no appreciable difference between an applied and sham treatment might look like a null effect, the result may actually confirm a bilateral therapeutic effect previously hypothesized to result from vector DNA transfer to the contralateral eye.

Some 38.7% experienced mild ocular adverse events, including cataracts, intraocular inflammation, and elevated intraocular pressure. Intraocular inflammation occurred in 16.7% of treated eyes between years two and five, down from 79.0% during the first two years.

Lenadogene nolparvovec gene therapy provided sustained bilateral visual improvements and demonstrated long-term safety in patients with MT-ND4-associated LHON.

Results suggest a lasting therapeutic benefit, making this approach a promising intervention for a condition with few treatment options. Future studies should further explore the contralateral effect and the therapy’s impact on younger populations.

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