Breakthrough in Gene-Editing Therapy for Leber’s Hereditary Optic Neuropathy

A research team led by Professor Hyunji Lee of the Department of Convergence Medicine at Korea University College of Medicine (co-first authors: PhD candidates Sanghun Kim, Ji Eun Kim, and Sungjin Ju; co-corresponding author: Professor Hyunji Lee) has successfully demonstrated the world’s first gene-editing treatment for Leber’s Hereditary Optic Neuropathy (LHON). The study was conducted in collaboration with Seoul National University College of Veterinary Medicine and Edgene Co., Ltd.

Leber’s Hereditary Optic Neuropathy is a maternally inherited mitochondrial disease that leads to rapid central vision loss and eventual blindness due to degeneration of optic nerve cells. It predominantly affects young men in their teens to thirties and is recognized globally as a major hereditary optic neuropathy, with an estimated 30,000 to 50,000 affected individuals worldwide.

LHON is caused by point mutations in mitochondrial DNA (mtDNA) complex I genes such as MT-ND4, ND1, and ND6. Among these, the m.G11778A mutation in MT-ND4 accounts for approximately 70% of all cases. However, gene therapy has long been considered infeasible because guide RNAs used in traditional CRISPR gene-editing systems cannot penetrate the mitochondria. Idebenone, currently the only approved treatment, provides limited temporary support for mitochondrial function and does not offer fundamental therapeutic benefit. As such, developing accurate disease models and curative genetic correction technologies has been an urgent global priority.

The research team successfully engineered the MT-ND4 G11778A-equivalent mutation (m.G11185A) in mice using high-fidelity DdCBE (Hifi-DdCBE), a mitochondrial base-editing platform. The resulting mouse model faithfully reproduced key pathological characteristics of human LHON, including thinning of the retinal ganglion cell layer, reduced ganglion cell numbers, and impaired visual function.

The team then applied a therapeutic approach using precision-enhanced TALE-linked deaminase (TALED-V28R), reported in Cell in 2024, delivered via adeno-associated virus (AAV). Intravitreal delivery of AAV-TALED-V28R successfully corrected the pathogenic mtDNA mutation in retinal ganglion cells. Retinal thickness and retinal ganglion cell counts were restored to normal levels, and visual function—assessed through OKN and ERG—showed marked improvement. Furthermore, application of TALED-V28R to patient-derived cells restored ATP production and mitochondrial complex I activity, further supporting its clinical translation potential.

Co-first author Sanghun Kim, PhD candidate, stated, “This research presents new possibilities and hope for patients who have long suffered from the lack of effective treatments,” adding, “We will continue to advance mitochondrial gene-editing technologies toward real-world clinical application.”

Professor Hyunji Lee, co-principal investigator and senior corresponding author, emphasized, “This is the world’s first study to demonstrate therapeutic efficacy of gene editing in a living model of mitochondrial disease.” She continued, “We hope that gene-editing therapies for mitochondrial disorders—including LHON—will progress to clinical application and eventually become commercially available treatments.”

This research was published in the prestigious international journal Nature Communications (Impact Factor 15.7) under the title “In Vivo Mitochondrial Base Editing Restores Genotype and Visual Function in a Mouse Model of LHON.”