Gene Therapy for Leber Hereditary Optic Neuropathy: Initial Results

Area of Science:

• Ophthalmology
• Genetics
• Neurology

Background:

• Leber hereditary optic neuropathy (LHON) is a mitochondrial disorder causing severe vision loss.
• The G11778A mutation in the mitochondrial ND4 gene is a common cause of LHON.
• Current treatments for LHON are limited.

Purpose of the Study:

• To evaluate the safety and tolerability of escalated doses of an adeno-associated virus vector (AAV) gene therapy.
• To assess the potential efficacy of AAV-mediated ND4 gene transfer in LHON patients.

Main Methods:

• A prospective, open-label, phase I gene therapy trial (NCT02161380).
• Intravitreal injection of scAAV2 vector expressing ND4 into one eye of 5 LHON patients.
• Dose escalation (low and medium) with safety and visual function assessments over 90-180 days.

Main Results:

• No serious adverse events were observed in the 5 participants.
• Visual acuity remained stable in 2 participants and improved by up to 3 lines in 2 others.
• Minor adverse events included transient IOP increase and keratitis; no vector DNA detected in blood.

Conclusions:

• AAV-based gene therapy for G11778A LHON appears safe and well-tolerated in this small cohort.
• Preliminary data suggest potential for vision improvement, warranting further investigation.
• Long-term follow-up is necessary to confirm these findings and assess sustained efficacy.