When will the blind regain their sight?

Svetlana Bozrova, "Biomolecule"
For references, including explanatory special terms, see the original article.

With the help of vision, a person perceives about 80% of information. The loss of any channel of perception of the surrounding world is a great tragedy for a person, but losing sight – the main supplier of external information – is especially unpleasant. Scientists around the world are puzzling over the solution to the problem of blindness – how to stop the loss of vision and how to return it to people who are already blind. And they are making significant progress. In 2016, the company RetroSense set up an experiment to restore vision in rats – and they succeeded. Let's see what they came up with.

Let's briefly recall how human vision works. In the human eye (and more specifically, in the retina) there are two types of photosensitive neurons, or photoreceptors – rods and cones (Fig. 1). Rods are responsible for night vision (vision in low light conditions), cones – for daytime. Cones are divided into three types depending on the sensitivity to light of different wavelengths and, accordingly, are responsible for color perception: some for the red region of the spectrum, others for the green, and others for the blue. Irritation of all three types of cones gives a person the perception of white color.

Figure 1. The structure of the retina

The light signal (a beam of photons) goes to photoreceptors that contain photosensitive opsin proteins (the rods contain the most famous of them – rhodopsin [1], and in cones different types of opsins perceive different colors). As a result of a series of photochemical transformations of the molecules of these pigments, the membrane potential of the rods/cones changes – light energy is thus converted into a nerve impulse, which is transmitted through bipolar cells to ganglion cells, and those, in turn, direct what they see to the brain. Some diseases cause the rods or cones to atrophy and stop working. The consequences of such changes are sad – the patient goes blind. One of these diseases is retinitis pigmentosa (RP). This pathology is hereditary and so far incurable. Currently, about one and a half million people in the world suffer from RP [2]. Agree, the figure is considerable.

Of course, no one is ready to accept the impending blindness, and doctors and patients are trying in every possible way to resist the disease. At the moment there are three possible solutions. Firstly, monoclonal antibodies can be injected into the eyes that suppress the pathological growth of vessels feeding the retina – ranibizumab (Lucentis) or aflibercept (Eylea). However, patients with retinitis pigmentosa, unlike patients with age-related macular degeneration, this medicine does not bring much benefit. The second way out is gene therapy. This option is currently suitable only for those people who have a mutation in the RPE65 gene. The treatment method developed by Spark Therapeutics is currently undergoing the third stage of clinical trials. Unfortunately, this method will not help patients who are already blind. The third option may be suitable as a last resort, but in fact few people will agree to a dangerous and expensive eye transplant operation. In addition, the patient will have to constantly carry an Argus 2 electronic device worth $ 150,000, which can also cause some inconvenience. A similar device combining holographic and optogenetic technologies with a cybernetic "prefix" has already been described on biomolecule [3], however, it is not much easier to live and interact with it than with Argus 2.

So, all three ways to restore vision are quite limited and inconvenient to use. So are any efforts futile? In fact, patients with a non-functioning retina should not despair: optogenetics will still come to their aid (Fig. 2).

Figure 2. How does optogenetics work? In the cell membranes of algae there is an ion channel (channel rhodopsin, ChR), which opens under the influence of blue light. With the help of genetic engineering methods, the gene of this channel protein can be inserted into specific neurons of the human brain. Neurons communicate by means of electrical signals – "waves" of polarization and depolarization of their membranes resulting from the opening/closing of ion channels. It is possible to control the "communication" of transgenic neurons producing channel rhodopsin with just flashes of blue light. Using the correct sequences of light pulses, you can take control of the activity of neural circuits and, for example, make an animal move.

Optogenetic neuron control technologies have been repeatedly discussed on the pages of biomolecules [4], [5]. Most often, they use a genetic vector based on an adeno-associated virus (AAV) produced by UniQure. This vector has already been approved for the treatment of hemophilia, Huntington's disease, cardiovascular diseases and chylomicronemia (hereditary lipoprotein lipase deficiency). If optogenetic tasks are solved, then the vector should deliver the bacteriorhodopsin gene to the retinal ganglion cells, which will make them photosensitive. Since our brain is plastic, it will soon learn to perceive signals coming directly from ganglion cells, and the patient can literally see the light. This scheme was recently developed by RetroSense and has already received FDA approval for the treatment of the first patient. By the way, Dmitry Kuzmin, a scientist and entrepreneur of Russian origin, recently became an investor in the company. The therapy scheme is quite simple – the patient needs to be injected into the eyeball once or only a few times in his life. The price of such an event is still unknown, but hopefully many patients will be able to afford it.

This successful development was preceded by another scientific breakthrough: scientists from the Salk Institute for Biological Research (Salk Institute) learned how to introduce genes not only into dividing, but also into postmitotic, "mature" cells – for example, cells of the eye, brain, pancreas or heart. In order to achieve their goal, the scientists used the well-known NHEJ repair pathway (non-homologous end-joining, non-homologous end-joining). In nature, this mechanism is used to repair DNA by simply "stitching" the ends of broken chains. In order to be able to insert the gene in the right place, a special approach was developed, which the researchers called HITI (homology-independent targeted integration, targeted integration independent of homology) [2], [6]. The HITI package consists of a cocktail of nucleic acids, which is delivered to neurons using a viral vector. In this way, scientists managed to partially restore vision to rats with retinitis pigmentosa caused by damage to the Mertk gene (encodes a transmembrane protein from the tyrosine kinase family, necessary for full-fledged phagocytosis in retinal pigment epithelium cells [7]). This technology looks promising for clinical situations that can be corrected by "fixing" specific defective genes.

Until recently, it was difficult to assume that blind people would have the opportunity to see clearly, but the future is coming at us with incredible speed and, apparently, brings us many victories over incurable diseases.

Literature

1. Biomolecule: Visual rhodopsin – a receptor that reacts to light;

2. New gene-editing technology partially restores vision in blind animals. (2016). ScienceDaily;

3. Biomolecule: Optogenetics + holography = epiphany?;

4. Biomolecule: Light-controlled anion channels detected;

5. Biomolecule: A light-controlled potassium channel has been created;

6. Keiichiro Suzuki et. al. (2016). In vivo genome editing via CRISPR/Cas9 mediated homology-independent targeted integration. Nature. 540, 144-149;

7. Emeline F. Nandrot et. al. (2012). Retinal pigment epithelial cells use a MerTK-dependent mechanism to limit the phagocytic particle binding activity of αvβ5 integrin. Biology of the Cell. 104, 326-341.

Portal "Eternal youth" http://vechnayamolodost.ru  17.04.2017