RESTORE study highlights persistent vision recovery in LHON patients with MT-ND4 mutation

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A large international study conducted by the LHON Study Group reported that a unilaterally administered gene therapy to treat Leber hereditary optic neuropathy (LHON) caused by the MT-ND4 gene variant resulted in bilateral improvement in visual acuity with improved quality of life and good overall tolerability up to 5 years after treatment.

The first study author, Patrick Yu-Wai-Man, MD, PhD, and colleagues commented, “These results demonstrated the persistent benefit over time from 1 dose of lenadogene nolparvovec (rAAV2/2-ND4, Lumevoq, GenSight Biologics SA), which is promising for the use of gene therapy in LHON due to the MT-ND4 gene variant,” the most common cause of LHON.

Yu-Wai-Man is from the Cambridge Centre for Brain Repair and MRC Mitochondrial Biology Unit, Department of Clinical Neurosciences, University of Cambridge, and the Cambridge Eye Unit, Addenbrooke’s Hospital, Cambridge University Hospitals, both in Cambridge, United Kingdom; and Moorfields Eye Hospital, and the Institute of Ophthalmology, University College London, both London.

LHON, a genetic disease that affects the retinal ganglion cells,² results in severe bilateral sequential vision loss.

The investigators explained, “Lenadogene nolparvovec, an adeno-associated virus (AAV)–based ocular gene therapy, was developed to treat patients carrying the m.11778G>A mitochondrial DNA gene variant. Its efficacy and safety have been evaluated in four clinical studies that showed an improvement in best-corrected visual acuity (BCVA) up to 2 years after administration and a good safety profile.^3-6

RESTORE study

The multinational, multicenter, prospective RESTORE Study is the 5-year follow-up study of the phase 3 clinical RESCUE and REVERSE Studies of lenadogene nolparvovec to treat vision loss from LHON due to the MT-ND4 mutation. The RESCUE Study evaluated the treatment up to 6 months after the onset of LHON⁴ and the REVERSE Study did the same from 7 months to 1 year.⁵

In the RESCUE and REVERSE Studies, the patients were treated with a intravitreous injection in 1 eye and a sham injection in the other eye. The main outcome measures were the best-corrected visual acuity (BCVA), quality of life using the National Eye Institute visual functioning questionnaire 25, and adverse events.

The RESTORE Study included 62 of 76 patients who were included in the RESCUE ad REVERSE Studies; 55 patients completed the 5-year examination. The investigators reported that the patients “sustained bilateral improvement in visual acuity with improved quality of life and good overall tolerability up to 5 years after unilateral lenadogene nolparvovec intravitreal administration in patients with LHON due to the MT-ND4 gene variant.”

The investigators concluded, “In this analysis of the RESTORE trial, the follow-up of patients with LHON due to the MT-ND4 gene variant unilaterally treated with lenadogene nolparvovec demonstrated a sustained bilateral improvement in BCVA and a good safety profile up to 5 years after treatment. This evidence of persistent benefit over time is promising for the use of gene therapy in these patients.”

References:

1. Yu-Wai-Man P, Newman NJ, Biousse V, et al. Five-year outcomes of lenadogene nolparvovec gene therapy in LHON. JAMA Ophthalmol. Published online December 19, 2024. doi:10.1001/jamaophthalmol.2024.5375

2. Yu-Wai-Man P, Griffiths PG, Chinnery PF. Mitochondrial optic neuropathies—disease mechanisms and therapeutic strategies. Prog Retin Eye Res. 2011;30:81-114. doi:10.1016/j.preteyeres.2010.11.002

3. Vignal-Clermont C, Girmens JF, Audo I, et al. Safety of intravitreal gene therapy for treatment of subjects with Leber hereditary optic neuropathy due to mutations in the mitochondrial ND4 gene: the REVEAL study. BioDrugs. 2021;35(2):201-214. doi:10.1007/s40259-021-00468-9

4. Newman NJ, Yu-Wai-Man P, Carelli V, et al.; LHON Study Group. Efficacy and safety of intravitreal gene therapy for Leber hereditary optic neuropathy treated within 6 Months of disease onset. Ophthalmology. 2021;128:649-660. doi:10.1016/j.ophtha.2020.12.012

5. Yu-Wai-Man P, Newman NJ, Carelli V, et al. Bilateral visual improvement with unilateral gene therapy injection for Leber hereditary optic neuropathy. Sci Transl Med. 2020;12(573):eaaz7423. doi:10.1126/scitranslmed.aaz7423

6. Newman NJ, Yu-Wai-Man P, Subramanian PS, et al.; LHON REFLECT Study Group. Randomized trial of bilateral gene therapy injection for m.11778G>A MT-ND4 Leber optic neuropathy. Brain. 2023;146:1328-1341. doi:10.1093/brain/awac421