Gene therapy for Leber's hereditary optic neuropathy appears highly promising for increasing the best-corrected visual acuity in this patient population.
This article was reviewed by Jiajia Yuan, PhD
Gene therapy for Leber’s hereditary optic neuropathy (LHON) seems to be the first promising treatment for the disease.
LHON, a maternally inherited disease, causes optic nerve atrophy that in most cases results in simultaneous or sequential bilateral visual loss. Disease onset typically happens in patients between 14 to 21 years of age.
The most frequently occurring offending mutation is ND4 that appears in about 90% of Chinese patients and in about 50% to 60% of U.S. patients, according to Jiajia Yuan, PhD, Tongjl Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
No treatment is currently available for this disease.
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Dr. Yuan and colleagues initially treated nine patients with LHON with gene therapy in 2011. With this first attempt, she reported seven of the nine patients had a significant improvement of 0.3 logarithm of the minimum angle of resolution (logMAR) VA at 36 months in the best-corrected visual acuity (BCVA).
“We saw a durable response in six of these patients out to 75 to 90 months after treatment,” she said. “In addition, a bilateral improvement was achieved, as also was observed by other groups investigating gene therapy.”
Gene therapy trial
These promising results prompted a second multicenter gene therapy trial that began in 2017 that include 149 Chinese patients and 10 Argentinian patients.
According to Dr. Yuan, the patients, who ranged in age from 7 to 45 years, received a fixed dose of 1 x 1010 mg/eye for all patients, regardless of age, Dr. Yuan explained.
“The treatment was found to be well tolerated and no severe adverse effects occurred,” she said.
Keratitis developed in one eye at one month and anterior inflammation in one eye at three months that were both considered to be unrelated to the treatment.
Ocular hypertension was the most common adverse event that developed in 27.04% of eyes that decreased slowly over time after cessation of the steroid.
A significant improvement in the BCVA occurred in 63.21% (67 of 106 patients) at 12 months. The rest of the patients had not reached the 12-month time point at the time of this report. Similar to the initial study, the patients showed bilateral improvement.
“This is a real-world study, in that there was no specific patient selection,” Dr. Yuan explained. “The patients’ ages spanned a wide range as did the time of disease onset and the pretreatment BCVA.”
An evaluation of only the Argentinian patients showed that all had improvement in the BCVA.
“These patients fared better overall than the other patients in the group, with the average improvement in the treated eye was 0.6 logMAR and the average improvement in the untreated eye was 0.9 logMAR,” Dr. Yuan pointed out.
Related: Gene therapy for LHON: Deciphering phase III data
Importantly, this improvement in the BCVA is highly relevant for the ability of patients to function well during everyday tasks.
And the researchers saw results with the patients that were treated.
Dr. Yuan related that three months after treatment, a patient was able to cook and watch sporting events on the computer.
Dr. Yuan noted that gene therapy is a promising approach for patients with LHON.
“Nine patients were treated in 2011 to 2012 and we continue to follow them,” she concluded. “This is the longest term data from human gene therapy to date.”
According to Dr. Yuan, nearly two-third of 106 patients who reached the 12-month follow-up point achieved a clinically significant improvement in the BCVA.
“Importantly, no serious adverse events occurred in the real-world studies,” she said. “We are very excited about the potential impact of gene therapy on this disease.”
Read more by Lynda Charters
Jiajia Yuan, PhD
This article is based on Dr. Yuan's presentation at the American Academy of Ophthalmology's 2019 annual meeting. Dr. Yuan has no financial interest in any aspect of this report.