Grow a nerve or insert an implant

How soon will we learn to regain sight?

Anton Soldatov, TASS

Once upon a time, in the event of the death of the retina of the eye, a person could only get a cane and a guide. But recently, biologists were able to partially restore vision to a man who went blind 20 years ago due to retinal dystrophy.

Up to 75% of the information about the world we get through the eyes. At the same time, these are probably the most fragile organs of our body. And if problems with the lens or cornea can be eliminated or compensated, then the destruction of the retina is most often a verdict. The retina cannot simply be "borrowed" from a donor, like a heart or lungs. This is a real biological computer that converts light into an electrical signal and sends it to the brain.

The retina consists of many layers of cells, each of which is important in its own way. The outer one – the pigment epithelium – nourishes the eye, and also filters the light that should enter the photosensitive elements. They, in turn, convert the light reflected from objects into signals for nerve cells. They are in the very depths and directly "communicate" with the brain.

In the last few years, vision restoration technologies – from prosthetics to cells grown in vitro – have been actively developed. Some of them have been tested on animals so far, and some have already been approved for use in the clinic. So people with progressive blindness have more and more hopes for a bright (literally) future.

Bionic eyes

Almost 30 years ago, Mark Humayun, a biomedical engineer from the University of Southern California, began experiments on electrical stimulation of the retina of blind people. He found that this procedure causes the sensation of light flashes, which were called phosphenes. Gradually, Humayun's team found out that cells process different signals in different ways. But the main thing is that they managed to achieve more accurate stimulation, as a result of which the neurons generated not just flashes, but outlines of objects.

From 2002 to 2004, researchers implanted bionic prostheses in six volunteers with complete or partial blindness in one eye. The first users of the device, known as Argus I (from the Greek word "all-seeing"), reported that they were able to perceive phosphenes, shapes of objects and even feel movement. Today, about 300 people are getting to know the world with this device. An improved model, Argus II, was approved by European regulatory authorities in 2011 for people with retinitis pigmentosa, a group of rare genetic diseases in which photosensitive cells die. Two years later, the United States did the same.

To install Argus II, a chip is implanted in the eye of patients, inside of which there is a grid of electrodes. A miniature video camera on the glasses sends signals to a special processor. It converts them into instructions, which are then transmitted to the implanted device wirelessly. The electrodes then stimulate nerve cells in the front of the retina. As a result, people can distinguish objects with high-contrast edges, such as doors or windows. And someone even deciphered large letters on the stands.

It is not possible to navigate with the help of a prosthesis right away. Users should train their brain to learn how to interpret information from the chip. They also have to get used to having to turn their head from side to side, because the prosthesis itself does not provide eye movement. In addition, it works only in good light, and can be "buggy". But even in this form, according to reviews, it is already radically changing the lives of blind patients.

The next generations of implants can already stimulate cells that are located deep in the retina. The picture turns out to be more accurate and richer. The German company Retina Implant has created an implant based on semiconductors that directly capture light entering the eye. Power is supplied from a portable device through a coil that is implanted under the skin above the ear. Alpha AMS, the current version of the system, has received regulatory approval in Europe for the same retinitis.

Now such devices have a limitation: it is necessary that working nerve cells still remain in the retina. In diseases that mainly affect photosensitive cells, such as retinitis pigmentosa, this usually happens. But when too many retinal cells die, as in advanced diabetic retinopathy and glaucoma, such implants cannot help.

Now Humayun and his colleagues are working on a system that sends signals directly to the brain, bypassing the eye. The idea is not new: in the 1970s, the American biomedical engineer William Dobell showed that phosphenes appear after direct stimulation of the visual cortex of the brain. But in practice, this mechanism has been implemented only in recent years. He also uses a video camera and a processor to transmit data. Only the chip is installed not on the retina, but directly on the cerebral cortex. 

While the device Orion was tested on six volunteers with limited or no perception of light due to eye injury, damage to the retina or optic nerve. "The results are good," Humayun believes. However, there are no detailed scientific publications yet. But the risks of brain surgery are much higher: the implant may not take root and even cause inflammation.

Gene therapy

If blindness is caused by a mutation in some gene, you can try to influence it specifically: "turn off" its defective copy in the body and replace it with a healthy one that will perform the necessary functions. Now such operations are performed with the help of a virus. It is modified in the laboratory so that it delivers the desired gene directly to the cells without harming them, and is injected into the organ. 

There are two main obstacles here: the waywardness of the virus itself, which may not act as scientists need, and the activity of the immune system, which will bind the viral particles before they fulfill their mission. But in this respect, the eye is an ideal target. Firstly, it is small and has almost no contact with other organs. And secondly, his immune system rarely attacks outsiders.

For the first time, gene therapy was tested on people with hereditary optic nerve atrophy due to a mutation in the RPE65 gene. This disease develops in the first years of life, often manifesting as chicken blindness, and then progresses to extensive vision loss, which begins at the periphery of the visual field. It affects about one in 40,000 children. Phase III clinical trials in 2017 were crowned with success: people with almost complete vision loss after treatment could see obstacles better and bypass them. In December of the same year, the therapy received approval from the American regulatory authority.

Luxturna was the first gene therapy to receive the green light for clinical use. But for now, this is an achievement at the level of cooking scrambled eggs, and the goal is to master the whole "cookbook". The fact is that for the development of the disease, a person must receive two defective copies of the RPE65 gene – one from each parent. This means that only one needs to be replaced for the cure. But in most cases, simply adding a normal copy of the gene will not help; it is necessary to "turn off" the mutated gene.

Gene therapy has other serious limitations. It is promising only for hereditary mutations and can develop according to the principle of "one drug – one target". Since more than 250 genes are involved in the development of blindness in one way or another, the number of possible therapeutic targets is huge. For example, more than 100 mutations in the RHO gene lead to retinitis pigmentosa, the most common hereditary retinal disease. Gene therapy is also useless in the later stages of the disease, in which the retina is almost destroyed.

Optogenetics

Unlike gene therapy, an optogenetic approach can be used at different stages of disease development. In optogenetics, the virus delivers genes to the cells of the eye that allow them to produce photosensitive proteins – opsins. The growth of opsins can restore some photosensitivity of damaged photoreceptors, or even make those cells that usually do not have this function sensitive to light.

A few years ago, scientists managed to restore the photosensitivity of cells (cones) affected by retinitis pigmentosa in mice. Of course, the mice themselves could not report the results, but the researchers were able to determine it indirectly by measuring the activity of retinal nerve cells, which are stimulated by cones when light hits them.

The weak point of this approach was that opsins work well only in bright light. But such conditions are not always achieved. But scientists managed to find a solution: to adapt special glasses that additionally stimulate retinal cells. This increases their sensitivity. As a result, the patient can see the silhouettes of large objects and objects. Last month, the results of trials of this dual system on a single patient were published in the leading scientific journal Nature Medicine.

One problem remains: opsin treatment does not work well in tandem with natural vision. If only some parts of the retina are destroyed, but vision is preserved in other areas, opsins can "illuminate" them and interfere with natural vision. In the future, scientists hope to modify opsins in such a way as to control their parameters.

Cell regeneration

A more complex, but in some sense, the most natural way is to grow organ cells from the patient's own tissues. To do this, bioengineers usually take a few living skin cells and turn them into stem cells – progenitor cells from which all the others are formed. In a bioreactor, the necessary eye cells are grown from them: photosensitive or nervous, depending on the disease.

Stem cells can potentially cure blindness even in the late stages. However, in practice, it is not so easy to "persuade" new cells to become part of an organ. The transplanted nerve cells should connect with their neighbors and start transmitting a signal. Animal studies have shown that only a small part of them are able to properly integrate into the retina.

The situation is simpler with the cells of the pigment epithelium. This is the outer layer that nourishes the eye and protects it from damage. Age–related macular dystrophy is one of the most common diagnoses of disorders of these cells. Today, they have already learned to recreate them well on animal models. To do this, scientists create special cell scaffolds, which are then transferred to the eye as part of a biogel. The gel dissolves, and the cellular "patch" grows into the eye and begins to work. In 2018, in America, pigmented epithelium grown in vitro was successfully implanted in four patients. All four of them stopped the deterioration of vision caused by the disease.

Another option so far sounds rather exotic – to try to initiate regeneration processes in existing cells. Most animals do not have this ability, but reptiles and some fish do. Thomas Reh, a neuroscientist at the University of Washington in Seattle, is trying to find the key to this ability in humans. And he has already received the first results.

In the early 2000s, Reh isolated cells that provide the structure of the retina and support its function. They, as he claims, are the "factories" for the production of new neurons in fish and reptiles. In 2015, he and his team raised genetically modified mice that were injected with a gene for the production of the protein Ascl1 – it is necessary for the production of those neurons in fish. Then the mice had their retinas damaged and waited for Ascl1 to start the regeneration process.

The experiment was not a complete success. No new neurons appeared in adult mice. But they appeared in the young! Subsequently, Nicholas Jorstad, a biochemist and graduate student in the Reha team, discovered that adult cells have a special enzyme that blocks their access to the Ascl1 gene. Reh's group set to work with a vengeance. In 2017, they were able to block the enzyme and ensure that regeneration began in adult mice as well. Although their structure was different from natural cells, tests showed that the new neurons are sensitive to light.

It will take another years to polish all the methods and get around the pitfalls. But today we are already at the stage of an "arms race". The question is not whether it is possible to restore vision even with complete loss. The question is who will do it better, faster and cheaper.

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