Gene therapy for degenerative retinal disease has no safety concerns but fails to improve vision loss

The 28-patient Phase 1 gene therapy clinical trial for degenerative retinal disease Leber hereditary optic neuropathy (LHON) found no significant safety concerns; However, with the highest dosage, treatment failed to improve or slow down vision loss. LHON affects the optic nerve, which carries visual signals from the light-sensitive retina to the brain. The study was sponsored by the National Eye Institute, a 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 that is used by cells to perform functions.

7LHON-related vision loss affects more men than women. The main symptom is a sudden loss of central vision, which often appears in young adulthood. About 95% of cases are caused by three different mutations, each of which causes excess production of reactive oxygen species from ATP synthesis. Scientists are unsure why retinal ganglion cells – the cells that make up the optic nerve – are particularly susceptible to the toxic effects of excess reactive oxygen species, which over time leads to dysfunction and death of the cells.

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

The researchers tested four therapeutic doses, each containing a different concentration of the gene vector. They then monitored trial participants for three years for adverse events, including changes in visual function, acuity, and immune response to treatment.

Treatment-related safety concerns were limited to the inflammatory eye condition uveitis, which was more likely with higher doses. Seventy percent of the participants who received the highest dose developed uveitis, compared to a total of 15% for all other groups combined.

Although gene therapy for Leber hereditary optic neuropathy appeared safe, we were unable to show that our approach had an effect on vision. Of note, in this clinical trial we chose to omit the prophylactic steroid treatment that is often administered with gene therapy to inhibit the immune response to the gene vector. “The observation informs future gene therapy trials of when prophylactic steroids are necessary and when they are not.”

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

Despite the therapy’s good safety profile, investigators were unable to show that it prevents vision loss. Some participants’ vision improved in the injected eye, the partner’s eye, or both. People with LHON are known to improve; However, participants with minimally affected vision (20/40 or better) at the time of enrollment did not have preserved vision, having lost approximately three lines of visual acuity during the first 12 months after injection, as on an eye chart. was measured.

According to the study investigators, although this gene therapy approach to LHON may provide visible benefit for some patients, the effect is minimal at best. Based on these findings, investigators have declined to pursue additional phases of clinical testing. They are now looking at alternative approaches, including gene editing of the mitochondrial genome.


National Institutes of Health

Journal Reference:

Lam, BL, and others. (2022) Leber hereditary optic neuropathy gene therapy: adverse events and visual acuity outcomes for all patient groups. American Journal of Ophthalmology.


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