Usher’s disease: how to defeat an incurable disease leading to blindness

A disease that is not immediately recognized

Usher syndrome (Usher) is a rare hereditary disease characterized by hearing loss and progressive and irreversible vision loss. At first, the disease can manifest itself as night blindness (that is, impaired vision in low light). As the disease progresses, peripheral (lateral) vision is gradually lost, limiting the visual field to tunnel vision and gradually leading to total blindness.

Sometimes the disease also affects the vestibular functions of a person. The mental state of people with this disease does not suffer, although in childhood they may experience learning difficulties due to hearing and vision impairment.

There are three types of Usher syndrome, and each type causes a different combination of health problems.

People with type 1 have severe hearing loss (only able to hear very loud sounds) or even deafness at birth. By about 10 years of age, they lose their night vision, and by mid-life they experience loss of vision altogether. In addition, they have balance problems, including problems with walking.

In the second type, hearing loss is moderate to severe in early childhood; night vision loss develops during adolescence and becomes severe by midlife. At the same time, a person has a normal balance of the body.

People with type 3 have normal hearing at birth, but hearing loss begins in childhood. The loss of night vision makes its debut in adolescence and also becomes serious by midlife. However, they also have no problems with body balance.

Types 1 and 2 are the most common.

According to Tatyana Avanesova, there are about 4-5 thousand such patients in the country, but the verification of the diagnosis is difficult: to confirm it, you need to undergo genetic testing, which is not included in the CHI, and not all patients are ready to pay for the analysis. “Let’s say a patient comes to the ENT, and the doctor is almost sure that in front of him is a person with Usher’s syndrome. Accurate diagnosis requires an expensive genetic study, and often patients refuse it, not only because it is expensive, but also do not see the point – it still cannot be treated … “

Ophthalmologists may suspect a disease based on the results of an examination of the fundus, on which certain pigments appear. “Such patients complain that they can’t see well at dusk; their fields of vision are narrowed. If hearing loss is added to this, there is every reason to suspect the diagnosis of “Usher’s syndrome,” continues Tatyana Andreevna.

According to the expert, it cannot be said that all Russian ophthalmologists are well aware of this syndrome, however, one cannot say that they are totally unaware of it either. As for the parents of such children, then, of course, at first they do not suspect anything: the child develops, like their peers. Suspicions that the child does not hear well do not begin immediately. “Sometimes children who do not hear simply understand what they want from them by the movement of their parents’ eyes: for example, when a child is asked to bring something and looks in that direction. It takes some time to understand that the baby does not hear well. And here it is important not to miss the moment in order to put a hearing aid on time for the child: this is necessary for the development of the speech apparatus. There are patients who do not speak at all, and there are those who speak poorly, but their parents understand them. Parents also have to go through stages of denial and acceptance that their child has a hearing problem. Then they accept the situation that the child will live with a hearing aid, that he must learn to listen in a team … And when all this happens, when the child turns 8–12 years old, they begin to notice that something is not right with him with vision,” says Tatyana Avanesova.

The doctor tells the story of one family from Tyumen: two children, a ninth grader and a university student, are engaged in carving – artistic cutting of vegetables and fruits. Mom, a doctor of functional diagnostics, says that from childhood they could not put their sons behind textbooks, they did not want to read. And only then the parents realized that it was just hard for children to read. Another mother of a child with Usher’s syndrome recalls that at night he got up to go to the toilet, but could not go back because he could not see anything in the dark: he walked to the room with a smartphone flashlight.

It is difficult to imagine what the parents of such children are going through. “I met with those whose children had just experienced visual impairment. And parents already know that blindness at the age of 30-40 is almost inevitable. And so today, parents are trying to give them maximum impressions in order to saturate their lives: they are taken everywhere, they show everything they can. There is a family in which four out of six children have Usher syndrome,” continues Dr. Avanesova.

The disease is autosomal recessive. Parents are only carriers of a mutation in the gene, which they do not even suspect, since they do not have any symptoms. And if two such carriers meet and start a family, the chances that they will have a child with the disease are 25%.

Our expert believes that the number of patients with Usher syndrome in reality can be ten times higher: “4-5 thousand are those who asked for help. But someone does not yet know about the disease, someone is embarrassed to seek help; someone does not know who to turn to, and someone finds it difficult to diagnose. Of course, the situation could be corrected by genetic screening: the gene has been known for a long time and is easily diagnosed. With the mass use of testing, the cost of analysis will inevitably decrease.”

Hope for gene therapy

Today, patients live in the hope that a drug that will save their sight and hearing will be developed. And the main promising developments that are underway in the world are related to gene therapy.

Scientists have no doubt that the future of medicine lies in gene therapy. After all, this direction, which is based on the principle of influencing the disease with the help of genes transferred into the cells of the patient’s body, unlike many methods of treatment, is aimed at eliminating the causes of the disease, and not its symptoms. In simple terms, a section of a gene or a gene is introduced into the body to replace the defective one with the help of a carrier – a gene vector. Gene therapy may involve trying to “fix” or replace a mutated gene, turn off a mutated gene that is causing a problem, or insert a normally functioning copy of a gene into cells to help the body produce a complete protein. Researchers are testing several approaches to gene therapy, including transfecting (introducing) a healthy copy of a gene, inactivating (or “turning off”) a mutated gene that is not functioning properly, and introducing a new gene into the body to fight disease.

The first drugs of this class have already appeared for the treatment of various ophthalmic pathologies – they are injected directly into the eye and help prevent the development of blindness. According to the head of the laboratory of molecular virology at Sechenov University, Alexander Malogolovkin, several research groups and companies are developing various gene therapy approaches for the treatment of Usher syndrome in the world. The first studies were started by the Dutch, where there is a large patient association. In the United States, the first developments in the field of gene therapy appeared in 2016. Russian scientists are also engaged in research in this area. And today they can boast of serious successes.

…Several years ago, Tatiana Avanesova met at a conference with ophthalmogeneticist Marianna Winner and patient Varvara Shibanova, who lives with Usher’s syndrome and has known about it since she was 20 years old. Varvara realized that as long as she sees, she can change something, she is helping patients with hereditary retinal diseases together with the NGO “To See”. Marianna Winner, a scientist, an enthusiast, together with the Retina Foundation, headed by Tatyana Avanesova, decided to apply for research funding to bigpharma. “We were ignored for six months. Previously, the patient community applied to the Ministry of Health, from where the refusal came: at the stage of ideas, the state does not participate financially, but this is world practice. On the other hand, where will the funds come from to test the hypothesis? Then we organized a fundraiser, raised 2.5 million rubles, although we needed more. But sanctions began, logistics changed, and it was decided to proceed from the realities. And on September 30, RetinaFond signed an agreement with Sechenov University on the development of gene therapy for the treatment of Usher syndrome,” says Tatyana Avanesova.

“I met Varvara and Kirill Baibarin, head of the To See, and these real patients were so worried that they see poorly, which I understood that we must do everything in our power to help them. Millions of dollars are spent on research in the world, but so far there has been no concrete success. But we still decided to start and move towards a specific goal in small steps. Now we have 7 people in our laboratory, these are young specialists from Moscow State University, the Physicotechnical Institute, and pharmaceuticals. In a short period of time, we have received two genetic constructs (drugs) for the replacement therapy of Usher syndrome based on mini-genes. To put it bluntly, a gene is broken in Usher syndrome, and we figured out how to deliver a special construct to the eye in order to “fix” it. For this, the substance is placed in the adeno-associated vector. Then the medicine is injected subretinally (under the retina): a special operation is performed for this. One dose is enough, and the effect should be long-term: from 3 to 5 years. So far, this is the only drug candidate with this mechanism of action for Usher’s syndrome. There is a similar one for another orphan disease, retinitis pigmentosa, today it costs 500 million rubles. But in fact, our patients have both gene retinitis and hearing loss, and we need another gene that should act on hearing loss, but above all, our goal is to save vision. It, of course, will not become the same, but it will be possible to stop the process of its loss,” says Alexander Malogolovkin.

The prospect of such treatment is also that it can completely save the eyesight of those who are not yet aware of the disease. That is why the task of genetic screening becomes even more urgent. After all, the sooner you start using such treatment in the future, the more likely it is to preserve vision in children with the syndrome of 10-12 years old.

However, so far the drug has been tested only on cell models in the laboratory. Scientists say that our genes work in vitro, that is, they synthesize the desired protein. The next stage is research on mouse models. Suppliers of blind mice have already been found (these are transgenic mice in which the gene was broken on purpose): they will have to check how the drug works. However, scientists need money for such research. And they really hope that there will be sponsors for this socially significant project. On the RetinaFond website, a collection has begun for the second stage of the study.

“Sometimes even the first stage of research seemed impossible. It is realistic to bring the day of the beginning of the second stage closer. Especially today, when all clinical trials of Western pharmaceutical companies in Russia have been completely stopped. And our developments are very important today. And we are keeping pace with European and American scientists, we are constantly in touch with them. They are moving in the same direction. But everything depends on finances: there is a laboratory, there is an understanding of where to go, there are talented scientists. And there are patients who live in hope. We only need material support,” says Alexander Malogolovkin.

Meanwhile, Tatyana Avanesova tells what parents should pay attention to in order to suspect Usher syndrome in a child in time:

“You need to watch how the child navigates in the dark. There are parents who take a violation of twilight vision, or simply “night blindness”, for something ordinary and normal. However, it is not. So, if at twilight children experience discomfort in behavior, in addition, children often touch objects, stumble, you should be wary. By the way, today in the city there are a lot of scooters abandoned anywhere – visually impaired people stumble over them. And further. When visual fields deteriorate, people who do not see from the sides turn their whole body to see the interlocutor – pay attention to this! And, of course, the combination of hearing loss, or hearing loss, and these symptoms, plus visual impairment itself, including blurred vision, are also alarming symptoms.