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Gene therapy of one eye improved vision in the other
Polina Loseva, N+1
Clinical trials of gene therapy against Leber's hereditary optic neuropathy ended with unexpected success: although participants were injected with the drug only in one eye, vision significantly improved in both. Later, the test organizers repeated this experiment on macaques and confirmed that the viral vector really migrates from one eye to another. But how he manages it is still unknown. The study was published in the journal Science Translational Medicine (Yu-Wai-Man et al., Bilateral visual improvement with unilateral gene therapy injection for Leber hereditary optic neuropathy).
Leber's optic neuropathy is a hereditary disease with an unfavorable prognosis. It is caused by a number of point mutations in mitochondrial DNA, which are particularly dangerous for retinal ganglion cells. These cells gradually die, and with them the optic nerve degrades. Therefore, a person can lose sight almost completely in just a year after the first symptoms appear.
Today, for Leber neuropathy, as for many hereditary diseases, there is no reliable treatment – only a drug that supports mitochondrial function in the early stages of the disease. It would be possible to change the situation radically with the help of gene therapy – that is, to introduce a healthy copy of the gene into ganglion cells. According to this principle, drugs are already working against another eye disease – Leber's amaurosis – which affects the photoreceptors of the retina. However, in this case it is easier to solve the problem, since the mutated gene is located in the nuclear DNA.
An international team of scientists led by Jose-Alain Sahel has developed a way to repair a mitochondrial defect using gene therapy. The researchers constructed an adenoviral vector with the necessary gene, and in the protein that it encodes, they embedded a signal of mitochondrial localization – that is, a label that will allow it to get inside the mitochondria from the cytoplasm.
Now the researchers have reported on the third phase of clinical trials of their therapy. For her, they selected 37 patients, each of whom was injected with a real drug in one eye and a placebo in the other, and the eyes were chosen randomly, so that neither the patients themselves nor the doctors knew what got into which eye.
According to the organizers of the trials, one of the eyes was supposed to serve as a control for the second, and the difference between their condition was an indicator of the effectiveness of therapy. However, when it came time to summarize, they found that the eyes into which the placebo was injected also began to see better on average, and the differences between the two groups of eyes turned out to be insignificant (p = 0.894). Overall, vision improved significantly in 62 percent of the eyes that received the drug and 43 percent of the eyes that received a placebo. At the same time, 68 percent of patients in two years began to see at least one eye better, of which two people had it was not the eye into which the drug was injected.
Improvement of vision in the group of control and experimental eyes over two years of observation. A drawing from the article by Yu-Wai-Man et al.
Eye diseases do not just become a target for developing new methods of treatment – the eye is considered an immunoprivileged organ separated from the systemic blood flow by reliable barriers. This is what allows scientists to inject viral vectors into it or plant stem cells without fear of harming the rest of the body or growing a tumor with metastases. The more surprising was the result of this test: if vision has improved in the second eye, then there must be some communication routes between the two eyes.
To confirm their assumptions, the researchers conducted a similar experiment on macaques. They injected one animal with a placebo in one of the eyes, and three others with an adenovirus drug. Three months later, adenovirus vectors were detected in the intact eyes of all three animals: traces of characteristic DNA were found in the retina and optic nerve. Based on this, the authors concluded that the improvement of vision in patients during a clinical study may be due to the migration of the drug from one eye to another.
It is still unknown how adenovirus vectors move between the eyes. The researchers themselves note that in trials of other gene therapy drugs for eye diseases, such effects have not been detected before. They also suggest that there may be several ways of migration of adenovirus DNA: it could get from eye to eye through the bloodstream as part of the vector itself or already modified mitochondria, or it could go a longer way – through the brain along the processes of neurons.
The design of this experiment does not allow us to find out exactly how gene therapy drugs travel between the eyes. However, judging by the fact that both for humans and macaques, the treatment turned out to be safe and did not cause any serious side effects, the appearance of tumors, or any other negative health consequences, we can conclude that gene therapy remains safe for people with eye diseases - even if the barrier between the eye and the rest of the body in fact, it turns out to be more fragile than previously thought.
In 2020, eye diseases were also treated with CRISPR/Cas – and this was the first time that a genetic editing system was introduced to patients in vivo. In addition, recently, for the first time, it was possible to restore visual acuity in mice after glaucoma – by reprogramming cells.
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