Looking for the exit of the tunnel
The journey of life involves many tunnels. Imagine now that, on this journey, you have entered a very long tunnel. Look back and the light at the entrance is getting smaller and smaller, it’s getting farther and farther away and you don’t see the exit of the tunnel, everything is getting dark. This is what happens to the person with choroideremia. It is a degenerative genetic disease that leads to vision loss. The retina loses its function, from the outside to the inside, it closes as in a tunnel and in the end, total darkness prevails.
Amaia and Fran do not have choroideremia but are well aware of the disease.
AMAIA AND FRAN; Choroideremia Association: Andoni, Ibon, Janire, Javier.
Fran and Amaia’s three sons have a choroideremia and their daughter is a conductor. It all started eight years ago. During a review of one of the children with glasses, the ophthalmologist saw something strange in the retina, some suspicious spots.
AMAIA ELGEZABAL; Choroideremia Association: in 2007 we were told that we had retinitis pigmentosa and shortly after we did a genetic analysis and we were told that it was choroideremia. In the beginning there was no fight, we were very sad and bad, there were hard times.
FRAN OLEA; Choroideremia Association: When we discovered that we had coronederemia, it was said that there was only one case of 250,000 people, and we said that all the cases of the Basque autonomous community were in our house.
Because if we look at the numbers, choroideremia is a rare disease. But as knowledge deepens, the number of cases increases. The amount that is used now is one case out of 100.00: not so rare.
FRAN OLEA; Choroideremia Association: If that were so. There can be 400 and piku people with choroideremia at the national level.
Here, the cases of the sons of Fran and Amaia were diagnosed in the Crosses. This is a common test for observing the inside of the eye. You look through the pupil's hole to see what's going on in the retina.
IÑAKI LETURIA; Elhuyar: This is my retina?MARTA
GALDOS; ophthalmologist: Oh, yeah,
yeah. IÑAKI LETURIA; Elhuyar: And is it healthy?MARTA
GALDOS; ophthalmologist: Oh, that's perfectly normal.
IÑAKI LETURIA; Elhuyar: What is a normal retina, what are its characteristics? MARTA
GALDOS; ophthalmologist: The retina must have an orange color, this is the middle zone, slightly darker and this lighter zone is called the phobic flare. This is the optic nerve, normal, blood vessels also have a normal thickness and there is no problem of pigmentation, you look at
that. IÑAKI LETURIA; Elhuyar: And for comparison it is necessary to see a retina with choroideremia.
MARTA GALDOS; ophthalmologist: we see the bottom of the retina of a 13-year-old boy. This image caused the diagnosis. he came first when he was 8 years old and now he's 13. There is pigmentation, some diffuse granules. Pigment alterations are observed in the color of said
granules. IÑAKI LETURIA; Elhuyar: What points that look like rust.
MARTA GALDOS; ophthalmologist: They look like that too, yeah. On the outside they are particularly noticeable, but half of them are also shown.
These areas in the form of stains or rust are due to the accumulation of debris in the retina. But why does this happen? Those with choroideremia lack a protein, a protein called REP-1, that is essential in the process of extracting and disposing of residues that are generated in the normal functioning of cells. What this does is, simply explained, to mark the bags or sticks of dirt that are formed to indicate that they must be removed from the cell. In the absence of protein or if the process is inefficient, debris accumulates and degeneration occurs. There is still no way to stop the degeneration: the choroideremia has no cure for today.
MARTA GALDOS; ophthalmologist: This disease affects two layers in the retina, the pygmy epithelium and the choriocapillaris. The retina is a group of cells that interact, the degeneration of one layer leads to the degeneration of another, since they are all linked, so that the entire retina degenerates. Eventually, photoreceptor cells, which convert light into electricity to emit images, begin to suffer because the pygmy epithelium is very important to keep these cells alive. This disease affects cones and sticks, but more sticks, resulting in the loss of night vision and peripheral vision. We don’t know why, we don’t know what makes the last one touch the macula or the center, but it is: the loss of vision and degeneration goes from the outside to the inside.
Thus, the first symptom of choroideremia is the difficulty of seeing in low light. At the same time, the field of view decreases with the passing of the years. But the mere presence of stains or the loss of vision as if the tunnel were closing does not mean that it is a choroideremia. Retinitis pigmentosa also has the same symptoms. Genetic tests must be done to confirm the presence of choroideremia. These are images of the last session held by the Spanish Choroideremia association. It was in Vitoria in the autumn. All members have had to go through the trance of genetic testing.
MARTA GALDOS; ophthalmologist: we are now seeing a 15-year-old boy with choroideremia. The spots of degeneration are evident, the atrophy is evident, the granules mentioned above are more abundant and in addition the fabric is bleached along with
the degeneration. IÑAKI LETURIA; Elhuyar: How would this retina look or see?MARTA
GALDOS; ophthalmologist: The back pole, which retains the central zone of sight, can therefore see well, but at night, in low light, it will cost you, and at the same time the field of sight is closing.
BENITO ROMERO; patient with choroideremia: At night it looks very bad, often you need help, whether you know the place or not, you are more relaxed or restless. During the day, I have no problems. Trouble starts at night when the sun goes down.
MARTA GALDOS; ophthalmologist: This retina is almost completely white, because the natural tissue has disappeared and has become almost transparent, from the inside you see the sclera, which we call the white of the eye. That's variable, there's no exact date. Some patients have done so by age 30 and others by age 50. This case is about 40 years old and legally blind, what does that mean? With the field of view almost closed, it only has tunnel vision.
ERNESTO MESA; patient with choroideremia: They see 10% of this eye and 70% of it, and their field of view is quite reduced, about 10 degrees, however I don’t need anyone’s help, and I even drive, I renewed my license a few months ago. I have more problems at night but I am still able to take the car because it has lights. If I had myself in the light on my legs or glasses!
Degenerative and genetic are the two surnames of choroideremia, that is, the worsening of the disease, which originates in genes, rather a single gene. The CHM gene on the X chromosome is responsible for the production of the REP-1 protein. Retinal degeneration begins when it is absent, not expressed, or not expressed correctly, the accumulation of debris. And it is also transmitted, from parents to children, through defective X chromosomes, as Fran and Amaia know well. The affected one is one of the two X chromosomes of Amaia, and contrary to all statistics, it has passed the defective X chromosome to its four children.
FRAN OLEA; Choroideremia Association: That damaged chromosome that was touched at the time of creating the children, then when I joined mine to create the boys, XY, X was damaged, it was like that with all three, and when the girl was created, the same, even then, the damaged X entered on one side and on the other, X taken from me, so it is conductive, but not damaged.
If the mother has only one damaged X, the odds are that half of her children will receive the damaged X, but in the choroideremia draw the number of Fran and Amaia is four.
FRAN OLEA; Choroideremia Association: That's how we got it, but it's not bad luck, we have four kids! You don't know!
BENITO ROMERO; patient with choroideremia: My brother hasn't been affected and I've been affected. Somehow I’ve won the lottery, well... It’s not bad, it’s just a lesson of life, it’s put you in the obstacles that you have to overcome and if you get it, then you feel good.
Paradoxically, the cure can also come from the same route through which the disease comes. Gene missing or not working? Well, let's change the piece! It is not a joke, it is possible and it is done in many diseases. This technique is gene therapy. Researcher Viki Kalatzis, among others, works on gene therapy at the Monpelier Institute of Neuroscience. She attended the session of the Choroideremia Association explaining the possibilities of therapy.
Gene therapy is currently the most optimistic and realistic way to cure choroideremia. Choroideremia is also indicated for this type of therapy as it is a monogenetic disease, that is, it must be modified as it is a single piece. Retinitis pigmentosa is more difficult to treat in this way, sometimes it is monogenetic, but often there is a large number of genes involved and many still unidentified.
VIKI KALATZIS; Institute of Neuroscience of Montpellier: Gene therapy is to put the missing or not functioning gene back into the cell and this is usually done through a virus. We take the virus, we take out what makes us sick and put the gene to be inserted in its place. So the virus will infect the cells because it is a virus, but now, once inside the cell, it will produce the missing gene and the cell will work again because it has achieved what it was lacking.
In principle it seems simple, but after several years of work and thanks to the collaboration of many research groups around the world, including Viki, the first clinical trial has now arrived.
MARTA GALDOS; ophthalmologist: The first trials in Choroideremia have been conducted with older people, people who don’t have much to lose in the sessions. Safety has been a priority, and so tests have been carried out for over 35 years. On the one hand, safety has been guaranteed, which does not cause more damage than previously existed, and on the other hand, efficiency has also been observed, the response of the photoreceptors is better, there has been some rescue.
Because that's what gene therapy does, rescuing retinal cells, but repairing survivors, that's why it's advisable to do this treatment before the degeneration becomes too great, to do it in time. The gene therapy pathway, however, has only just begun, so it is imperative that, as gene therapy matures, we develop other strategies, have a plan B.
Jon Zarate is a researcher and collaborates with the Choroideremia Association.
JON ZARATE, Researcher at the Faculty of Pharmacy, UPV/EHU: What may be most convincing or effective among Plan B's is to seek complementary neuroprotection along with gene therapy, or to resort to neuroprotection during the maturation of such gene therapy.
These neuroprotectants, such as growth factors or proinsulin, would slow down degeneration and prevent retinal death. At present, the knowledge of such proteins is high and the investigation of dosage and modes of transport is mostly stopped. Here, for example, the amount by which a particular molecule has reached the cell surface is being measured.
JON ZARATE, Researcher at the Faculty of Pharmacy, UPV/EHU: If there are groups in the UPV who are working on this, not only for retinal diseases, perhaps more work has been done on diseases of the central nervous system, Alzheimer's, Parkinson's, which may have similarity or other diseases of the nervous system, but this can also be viable if there is a project and focus forces on it, this plan B can be viable.
But patients' time is limited. This film shows the journey of two brothers with choroideremia. They visit the places they want to see before they go blind, so that they can later remember these images. For someone with choroideremia, the word future has a different meaning. Hope is also a word that comes in the vocabulary of choroideremians.
AMAIA ELGEZABAL; Choroideremia Association:: There must always be hope until the end, and that is what we are
at. FRAN OLEA; Choroideremia Association:: But it is not necessary to have, ...
AMAIA ELGEZABAL; Choroideremia Association:: ...we have reasons to hope.
In the short term, gene therapy combined with neuroprotective therapy may be the most effective treatment, but what this pathway can provide remains to be seen. And there's no deadline: they are mentioned 3, 5, 10 years... It is also a plan C: the creation of artificial retinas.
VIKI KALATZIS; Institute of Neuroscience of Montpellier: We have taken cells from the skin of patients with choroideremia and we have told them, now you are not skin, we have gone back in time and transformed them into maternal cells that have the potential to be what they want, not just the epithelium, and from there, we have managed to make them become retinas. Thus, we have a model of a diseased retina for testing gene therapy on it, for example, and it may also be the starting point for cell therapy for future use.
With this photo, one of Fran and Amaia's sons won a contest. The image was proposed by them to finish the report: at the end of the tunnel, they see the light.
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