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José Manuel Muñoz
group Mente-Cerebro, Institute for Culture and Society (ICS), University of Navarra and researcher of the International Center for Neuroscience and Ethics (CINET), Tatiana Pérez de Guzmán el Bueno Foundation.
During the little more than fifteen years that optogenetics - the introduction of exogenous genes encoding light-sensitive proteins into certain cells - has been in existence, neuroscientists have begun to test it in invertebrates, fish, birds and rodents. Also, to a lesser extent, in non-human primates. The recent publication in Nature Medicine of the first case in which optogenetics has been successfully applied in humans is the umpteenth example of how important it is to value and, above all, to finance the basic research .
When the first microbial opsins were discovered half a century ago, surely no one imagined that these light-sensitive proteins would one day be used to excite or inhibit neurons and, by virtue of this, explore possible neurological treatments. So far, interesting results have already been obtained in the study of epilepsy, Parkinson's disease, addictions and aggression, to mention just a few examples.
Optogenetics has a special potential for the manipulation of brain activity, as it can act on very specific regions and activate or inhibit the neurons of interest with a high degree of precision. However, it usually requires a small craniotomy to implant the device that allows light to pass into the brain tissue. Therefore, it seems quite reasonable that the first human trials have been carried out by choosing another target: the retina.
The new study represents undeniable hope for the visually impaired, although there are important nuances that should not be ignored and that invite us to be very cautious. But let's start with the positive, which is of great significance.
Researchers, led by José-Alain Sahel, have succeeded in partially restoring the sight of a 58-year-old man, affected by retinitis pigmentosa since the age of 18 and only able to perceive the presence or absence of light. Retinitis -or retinitis pigmentosa- is a group of hereditary disorders characterized by the gradual loss of vision due to degeneration of the photoreceptors -cones and rods- of the retina.
The clinical essay consisted of giving the patient an intraocular injection that, thanks to the employment of an adenovirus vector, contained the sequence Genetics coding for ChrimsonR: an artificial derivative of an opsin from the green alga Chlamydomonas noctigama.
The sequence was integrated into the DNA of the ganglion cells of the retinal fovea, neurons that under normal conditions act as intermediaries between the photoreceptors and the brain. The aim was to make these cells perform the function of 'light receptors'. After this, the man used special glasses that converted the images of the outside world into monochromatic amber-colored images.
After seven months of visual training, he was able to begin to locate, touch and count certain objects. Adding to this good news is the fact that the improvement remained stable for several months, with no apparent side effects such as retinal lesions or intraocular inflammation.
The impact and relevance of this study are very high. Not only is it the first optogenetic essay with human beings published to date, but it also opens up a possible avenue in the search for therapies for a disease, retinitis pigmentosa, which is suffered by some two million people in the world and for the time being has no treatment.
Important limitations of the study
However, there are several important limitations that need to be taken into account to avoid falling into euphoria. First, we are dealing with a single case. Sahel and coworkers had designed their essay to be applied in several other patients, but the covid-19 pandemic has prevented them from doing so. Of course, much more information would be needed to find out whether the visual improvements are widespread or whether, unfortunately, this is an exceptional case.
Secondly, this is not a simple process: it took almost twelve months - about five months for the integration and expression Genetics of ChrimsonR, plus another seven months of visual training - before the patient began to experience improvements in his vision; moreover, these only occurred with the special glasses in place. So it's not just a matter of getting an eye injection and going home.
Thirdly, the patient's visual recovery was quite limited: in addition to having serious difficulties in perceiving small objects - in particular, a box of staples - his vision was monocolored, as he could only perceive the amber-colored images produced by his glasses. The reason for this is Biochemistry and involves a very important technical limitation: the maximum sensitivity of the opsin used is precisely for the amber color - that is, at a wavelength of 590 nm.
In fact, the different types of opsins used in optogenetics show different chromatic sensitivities. This means that, in order to achieve multicolor vision recovery, the combined use of different opsins seems to be necessary, something that has not been tested and whose consequences are therefore uncertain.
Fourth and finally, regardless of the success that this therapy might achieve in the future, it would only be applicable to a certain class blindness, namely that caused by retinitis pigmentosa. The study is not designed, for example, for the treatment of cortical blindness, which is due to lesions in the occipital lobe of the brain.
Expectation and caution
This is an encouraging finding , which may open up new therapeutic perspectives for a visual impairment that was previously untreatable and which, based on what has been observed, does not seem to have harmful effects in the short term deadline. However, new trials, many more data and long-term follow-ups deadline will be needed to know whether procedure is sufficiently safe and effective.
Moreover, spectacular improvements are not to be expected - at least for the time being - but rather restricted to a limited perception of objects, and in one color only. Of course, it is not difficult to imagine that this already seems like a big step for those who, unfortunately, are partially or totally blind due to retinitis pigmentosa, but one should be very cautious.
We will still have to wait a long time to find out whether optogenetics can be used intracranially in humans, in the hope of finding treatments for certain neurological disorders. This is something that only time, opsins and, above all, the efforts of scientists and patients can lead us to find out.