Vector of change: scientists have made a breakthrough in treating hereditary blindness

Russian scientists have made a breakthrough in the research of therapy for hereditary blindness caused by Usher syndrome, a genetic pathology in which a person's hearing and peripheral vision gradually decrease. A drug that would stop this process is not yet available either in Russia or in the world. Researchers at Sechenov University have figured out how to deliver healthy copies of the damaged gene to retinal cells and stop the progress of the disease. They have successfully tested their development on laboratory mice. Read more about how the innovative drug works - in the material "Izvestia".

What is Usher syndrome

In the laboratory of molecular virology of the First Moscow State Medical University named after I.M. Sechenov are developing an innovative genotherapeutic drug for the treatment of Usher syndrome - an inherited disease of the retina, in which a person gradually loses vision. The drug based on viral vectors delivers a healthy minicopy of the gene (USH2A), "broken" in Usher syndrome, to retinal cells and thus stops the development of the disease. Earlier the development was tested in the laboratory on human retinal cells. Now scientists have tested the drug on laboratory transgenic mice and received the first encouraging results. The work was initiated jointly with and is supported by the RetinaFoundation for Research and Treatment of Retinal Diseases.

Researchers at the Laboratory of Molecular Virology have figured out how to deliver healthy copies of the damaged gene to retinal cells and stop the progression of the disease. They used viral vectors as "couriers" for this purpose. Namely, adeno-associated viruses (AAV), which are safe for humans and do not multiply in the body and do not cause disease.

Photo: Sechenov University Press Service

- Together with our colleagues from the RetinaFoundation for Research and Treatment of Retinal Diseases, the interregional public organization "To See" and ophthalmogenetic doctors, we have identified two hereditary retinal diseases for our further research. These are Usher syndrome type 2 and Stargardt's disease," said Alexander Malogolovkin, head of the laboratory. - Both diseases are categorized as orphan diseases. However, these pathologies lead to disability of patients, and at working age.

The researchers worked out the technology of obtaining viral vectors, their purification and concentration, as well as created a unique genetic construct and "packed" it into viral vectors. Earlier the development was tested in laboratory conditions on cell culture of human retinal pigment epithelium. The result confirmed the ability of viral vectors to deliver copies of the gene into cells. And now another important stage of the research has been completed - the new technology of genetic material delivery to retinal cells was tested on laboratory transgenic animals.

A drug for hereditary blindness

Genetically modified mice for the experiment were delivered from China. Using the genomic editing method, Chinese partners specifically "broke" the USH2A gene in the animals, which leads to the progressive development of Usher syndrome. During the experiment, the mice were divided into several experimental groups. The first group was injected with viral vectors carrying healthy mini-copies of the gene via subretinal injections. In addition to viral vectors, the second group was injected with viruses encoding green fluorescent protein (GFP) to make sure that the gene copies were successfully delivered to the retinal cells. A third control group of animals was injected with saline. The animals were monitored for several months, after which optical coherence tomography, histologic and molecular studies were performed.

Photo: IZVESTIA/Sergey Lantyukhov

At the end of the experiment, immunohistochemical studies of retinal samples of the animals were performed. They showed that in the mice, to which the gene therapy drug was delivered, it was possible to slow down the development of degenerative changes of the retina in Usher syndrome. Delivered healthy mini-copies of the gene stimulated the production of a protein that took over the function lost due to the mutation.

As Alexander Malogolovkin emphasized, the genotherapeutic drug being developed in the laboratory will not restore sight to people who have already lost it. It is aimed at slowing down the development of blindness in Usher syndrome and completely stopping the loss of vision in patients who do not yet have manifestations of this genetic disease.

Certainly, the approach described in the article is promising, as the genotherapeutic treatment reduces the risk of disability of patients, Nadiya Yunusova, an ophthalmologist at the CenterPlus Clinic of Infectious Diseases of the Federal Budgetary Research Institute of Epidemiology of Rospotrebnadzor, told Izvestia.

- The prospect of such treatment is also in the fact that it will be able to completely save the eyesight of those who do not yet suspect the disease. In fact, the earlier we start to apply such treatment in the future, the more chances to save eyesight in children of 10-12 years old with Usher syndrome, - she said.

Photo: Sechenov University Press Service

The prevalence of Usher syndrome ranges from 4 to 17 per 100,000 people and is represented by three clinical subtypes: USH1, USH2 and USH3, which differ in the severity of hearing impairment, the presence or absence of vestibular dysfunction and the onset of retinitis pigmentosa, said Elvira Shikhalieva, an ophthalmologist and physician at the Semeynaya Clinic. In turn, retinitis pigmentosa is a genetic disease, which is clinically manifested by gradual narrowing of the field of vision up to the onset of total blindness.

- In my opinion, a promising study, especially given the fact that the disease affects the able-bodied part of the population and to date there is no effective way to treat this pathology, - she said.

In the future, the developers plan to conduct large-scale studies on a larger number of animals with Usher syndrome - to select the exact dosage of the drug in mice of different age groups. In addition, in the near future, the researchers will conduct an experiment on laboratory models with Stargardt's disease - an inherited disease of the retina, which leads to loss of central vision. Using the same approach, the animals will be injected into the retina with viral vectors that will deliver healthy copies of the damaged gene into the cells.

The Laboratory of Molecular Virology was established in 2022 as part of the Priority 2030 strategic academic leadership program. The main areas of its work are gene therapy and immunotherapy.