Gene Therapy Offers Hope for LHON Patients

A multinational study by the LHON Study Group has reported sustained visual improvements and a favorable safety profile five years after treatment with lenadogene nolparvovec, an adeno-associated virus (AAV)-based gene therapy. This therapy targets Leber hereditary optic neuropathy (LHON) caused by the MT-ND4 gene mutation.

Understanding LHON

LHON, primarily caused by the MT-ND4 gene mutation in mitochondrial DNA, leads to acute and severe bilateral vision loss, mainly affecting the retinal ganglion cells responsible for transmitting visual signals from the retina to the brain.

Lenadogene nolparvovec was designed to address LHON and has previously shown promising results in improving vision during earlier clinical studies.

Study Design and Methodology

The study, titled "Single-Eye Gene Therapy for Leber Hereditary Optic Neuropathy," was published in JAMA Ophthalmology and included long-term data from the RESTORE study, which followed up on two earlier Phase III trials, RESCUE and REVERSE.

Treatment Approach

Participants in RESCUE and REVERSE received:

• A single intravitreal injection of lenadogene nolparvovec in one eye.

• A sham injection in the other eye.

The trials included patients with MT-ND4 mutation-associated LHON who experienced vision loss either:

• Within six months of treatment (RESCUE).

• Between six to 12 months prior to treatment (REVERSE).

Following the initial two-year trials, patients were monitored for an additional three years under the RESTORE study.

Patient Enrollment

• Initial Trials: 76 patients treated.

• RESTORE: 62 enrolled, 55 completed the five-year follow-up.

Assessments and Measurements

• Visual Acuity: Measured using logMAR (logarithm of the minimum angle of resolution).

• Quality of Life (QoL): Evaluated using the National Eye Institute Visual Functioning Questionnaire-25 (NEI VFQ-25).

• Safety Monitoring: Focused on ocular and systemic adverse events.

Key Findings

Sustained Visual Improvements

• Baseline BCVA (Best-Corrected Visual Acuity): 1.5 logMAR (20/600 Snellen).

• Two-Year BCVA: Improved to 1.4 logMAR (20/500).

• Five-Year BCVA: Remained stable at 1.4 logMAR.

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

Clinically significant recovery, defined as at least a −0.3 logMAR improvement (+3 lines), was observed in 66.1% of participants.

Quality of Life Gains

Participants reported substantial QoL improvements in seven of 10 NEI VFQ-25 subscales, including mental health and role difficulties. The composite score increased by seven points.

Contralateral Effect Hypothesis

Interestingly, no significant differences were observed between treated and sham eyes. Researchers suggest this supports a bilateral therapeutic effect, potentially caused by vector DNA transfer to the untreated eye.

Safety Profile

• Mild Ocular Adverse Events: Reported in 38.7% of patients, including cataracts, intraocular inflammation, and elevated intraocular pressure.

• Intraocular Inflammation:

- Occurred in 16.7% of treated eyes between years two and five.

- Marked improvement from 79.0% during the first two years.

Conclusion

The results from this study demonstrate that lenadogene nolparvovec gene therapy provides sustained bilateral visual improvements and long-term safety for patients with MT-ND4-associated LHON.

The findings highlight the therapy’s lasting therapeutic benefits and its potential as a promising intervention for a condition with limited treatment options.

Resources:

Patrick Yu-Wai-Man et al, Five-Year Outcomes of Lenadogene Nolparvovec Gene Therapy in Leber Hereditary Optic Neuropathy, JAMA Ophthalmology (2024). DOI: 10.1001/jamaophthalmol.2024.5375

Hendrik P. N. Scholl et al, Single-Eye Gene Therapy for Leber Hereditary Optic Neuropathy, JAMA Ophthalmology (2024). DOI: 10.1001/jamaophthalmol.2024.5618