Pathologically Responsive Mitochondrial Gene Therapy in an Allotopic Expression‐Independent Manner Cures Leber's Hereditary Optic Neuropathy

Background: During the first few trials of gene therapy for Leber’s hereditary optic neuropathy performed by our group, the visual acuity of the patients increased gradually over several months, or even years. However, in the current round of gene therapy for Leber’s hereditary optic neuropathy, we noted that the visual acuity of three patients increased rapidly, within a few days after treatment. Case presentation: Three patients who were diagnosed with mitochondrial gene 11778 mutation (associated with a G-to-A transition at Mt-11778 in the ND4 subunit gene of complex I of mitochondrial DNA that changes an arginine to histidine at amino acid 340) by genetic diagnosis were followed up three times before gene therapy, which lasted for 1 year, without spontaneous improvement of vision. Visual acuity in one or both eyes of each of the three patients increased rapidly after the initial gene therapy treatment. Conclusions: We suspect that in some patients with Leber’s hereditary optic neuropathy, a portion of the retinal ganglion cells might remain in a “dormant” state for a certain period of time; these may be activated, within an optimal timeframe, during gene therapy for Leber’s hereditary optic neuropathy.

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Progress in Gene Therapy to Prevent Retinal Ganglion Cell Loss in Glaucoma and Leber’s Hereditary Optic Neuropathy

Neural Plasticity ◽

10.1155/2018/7108948 ◽

2018 ◽

Vol 2018 ◽

pp. 1-11 ◽

Cited By ~ 12

Author(s):

Sara E. Ratican ◽

Andrew Osborne ◽

Keith R. Martin

Keyword(s):

Gene Therapy ◽

Clinical Trials ◽

Optic Nerve ◽

Genome Editing ◽

Optic Neuropathy ◽

Single Gene ◽

Leber’S Hereditary Optic Neuropathy ◽

Leber's Hereditary Optic Neuropathy ◽

Potential Use ◽

Hereditary Optic Neuropathy

The eye is at the forefront of the application of gene therapy techniques to medicine. In the United States, a gene therapy treatment for Leber’s congenital amaurosis, a rare inherited retinal disease, recently became the first gene therapy to be approved by the FDA for the treatment of disease caused by mutations in a specific gene. Phase III clinical trials of gene therapy for other single-gene defect diseases of the retina and optic nerve are also currently underway. However, for optic nerve diseases not caused by single-gene defects, gene therapy strategies are likely to focus on slowing or preventing neuronal death through the expression of neuroprotective agents. In addition to these strategies, there has also been recent interest in the potential use of precise genome editing techniques to treat ocular disease. This review focuses on recent developments in gene therapy techniques for the treatment of glaucoma and Leber’s hereditary optic neuropathy (LHON). We discuss recent successes in clinical trials for the treatment of LHON using gene supplementation therapy, promising neuroprotective strategies that have been employed in animal models of glaucoma and the potential use of genome editing techniques in treating optic nerve disease.

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