Gene therapy for retinal degenerative diseases has no safety concerns, but cannot improve vision loss

Gene therapy for retinal degenerative diseases has no safety concerns, but cannot improve vision loss

A Phase 1 gene therapy clinical study in 28 patients with Leber hereditary optic neuropathy (LHON) degenerative retinal disease did not identify any significant safety concerns; however, treatment failed to improve or slow vision loss, even at the highest dose. LHON affects the optic nerve, which transmits visual signals from the retina sensing light to the brain. The study was partly sponsored by the National Eye Institute, part of the National Institutes of Health.

LHON is caused by DNA mutations in mitochondria – cellular components called organelles that convert nutrients obtained from food into a form of energy called ATP, which cells use to function.

7LHON-related vision loss affects more men than women. The main symptom is a sudden loss of central vision, which often occurs in young adulthood. About 95% of cases are caused by three different mutations, each of which causes an overproduction of reactive oxygen species from ATP synthesis. Researchers are not sure why retinal ganglion cells – the cells that make up the optic nerve – are particularly prone to the toxic effects of excess reactive oxygen species, leading to cell dysfunction and death over time.

The therapy was designed to restore ND4 gene function by injecting a viral vector (AAV2) carrying the normal gene into the left or right eye of the participants. Once the vector is injected, it stores the gene in retinal ganglion cells, where it is incorporated into the cell’s nuclear DNA.

The researchers tested four therapeutic doses, each with a different concentration of gene vector. They then followed study participants for up to three years for side effects, changes in visual function, including sharpness, and immune response to treatment.

Treatment-related safety concerns were limited to inflammatory ocular uveitis, which was more likely at higher doses. 71 percent of the participants who received the highest dose developed uveitis, compared with only 15% in all other groups combined.

Although gene therapy for Leber’s inherited optic neuropathy seemed safe, we were unable to demonstrate that our approach affected vision. It should be noted that in this clinical study, we decided to abandon prophylactic treatment with steroids, which is often given with gene therapy, to prevent an immune response to the gene vector, “Lam said.” Observations inform future gene therapy studies when prophylactic steroids are necessary and when they are not. “

Byron Lam, MD, lead author, University of Miami Bascom Palmer Eye Institute

Despite the good safety profile of the therapy, investigators have not been able to demonstrate that it prevents vision loss. Some participants had improved vision in the injected eye, the other eye, or both. People with LHON are known to improve; however, participants with the least impaired vision (20/40 or better) did not retain vision at the time of enrollment and lost about three lines of visual acuity, as measured on the eye chart, during the first 12 months after injection.

Although this approach to gene therapy in LHON may bring visual benefits to some patients, the study found that the effect was modest at best. Based on these findings, the researchers refused to conduct further phases of clinical testing. They are now exploring alternative approaches, including genetic engineering of the mitochondrial genome.


National Institutes of Health

Diary link:

Lam, BL, et al. (2022) Leber’s gene therapy hereditary optic neuropathy: Adverse events and visual acuity outcomes in all patient groups. American Journal of Ophthalmology.

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