In a landmark phase 3 clinical trial, the international team successfully treated 37 patients with a new gene therapy who suffering from Leber hereditary optic neuropathy (LHON). Revolutionary gene therapy treating patients with a common form of mitochondrial blindness, and the results surprised them – despite treating only one eye, the gene therapy improved vision in both eyes in 78% of participants. The results suggest the gene therapy is incredibly promising for a condition in which most legally-blind patients would never recover their vision. Subject to further trials, the gene therapy could help thousands of people across the world to regain and retain some of their sight.
Phase 3 Clinical Trial
Conducted on 37 patients with LHON, the trial involved a gene therapy using a virus vector to modify genes within the patient’s retinal cells. The results were published in the journal Science Translational Medicine.
LHON affects a specific type of retinal cells, known as retinal ganglion cells, causing optic nerve degeneration and rapidly worsening vision in both eyes. Within a few weeks of disease onset, the vision of most people affected deteriorates to levels at which they are considered legally blind. Visual recovery occurs in less than 20% of cases and few achieve vision better than 20/200 (largest letter on a standard eye chart). LHON affects approximately 1 in 30,000 people, mostly men, with symptoms usually emerging in their 20s and 30s. The majority of patients carry the m.11778G>A mutation in the MT-ND4 gene. Existing treatment for this blinding optic neuropathy remains limited.
“As someone who treats these young patients, I get very frustrated about the lack of effective therapies,” said senior investigator Dr Sahel, a professor of ophthalmology at the University of Pittsburgh. “These patients rapidly lose vision in the course of a few weeks to a couple of months. Our study provides a big hope for treating this blinding disease in young adults.”
The treatment aims at correcting a common mutation within the MT-ND4 gene. MT-ND4 is a core subunit in a protein associated with mitochondria, and a mutation marked m. 11778G>A is thought to be associated with blinding neuropathy. Similarly, mutations in MT-ND4 may also be related to several other brain conditions, although these are not the same as the mutation targeted in this study.
37 patients were injected with the adenovirus-based therapy in one eye and a ‘sham’ injection (a placebo or, in this case, fake injection) into the other. The trial was randomized and double-blind across multiple centres, which make it the gold-standard of clinical trials. After 48 and 96 weeks, the participants were tested for vision changes and whether they showed signs of improvement using a standard Snellen eye chart (the ones with rows of smaller and smaller letters).
The researchers found that, on average, vision was improved by 15 letters (3 lines on the chart) after 96 weeks, which is an extremely impressive result. However, to the surprise of the researchers, the sham-treated eyes also saw an average improvement of 13 letters. Those that were in the early stages of disease and still losing their vision when they joined the study saw an even better improvement, being able to see 28.5 letters more in the treated eyes on average.
Unexpectedly Improves Vision in Both Eyes
“We expected vision to improve in the eyes treated with the gene therapy vector only. Rather unexpectedly, both eyes improved for 78% of patients in the trial following the same trajectory over 2 years of follow-up.” Said Dr Yu-Wai-Man, neuro-ophthalmologist at Cambridge’s Department of Clinical Neuroscience.
To decipher how this treatment improved both eyes, the researchers conducted a subsequent study on primates. After injection in the same way as the study above, they found the viral vector was present in cells throughout the eye that was not treated, although the mechanism in which this occurs needs confirmation.The researchers suggest that the viral vector may have transferred across neurones via interocular diffusion, and hence there was an improvement in vision in both eyes.
The results suggest an extremely promising new treatment for a rare but debilitating form of blindness. Further trials are expected to take place to confirm the results, and there are some outstanding limitations of the trial. For example, there was not a control group with this exact mutation, so the researchers could not directly compare to the treatment.
“Saving sight with gene therapy is now a reality. The treatment has been shown to be safe and we are currently exploring the optimal therapeutic window” said Dr Yu-Wai-Man.