A few months after the birth of their second daughter, whom they named Abril, Daniel and María Montaña decided to resort to increasingly noisy experiments. First they closed doors, then they slammed doors, played loud music, and popped balloons without warning. But their daughter didn’t even flinch, to the surprise of her older sister, María, who was startled every time. Some time later, in November 2023, doctors confirmed that the girl could barely hear and that her hearing loss would increase. The culprit, they were told, was a rare genetic mutation that affects a gene essential for sound to reach the brain.
April is 15 months old. She wears her hair in a ponytail, has a very fixed gaze and walks around with determination. You have to look very closely to notice that she does not respond to your voice, only to eye contact. At six months she was able to babble “daddy” and “mommy”, but soon after she stopped talking suddenly. The parents were surprised because there is no family history of this. But the doctors told them that each of them has a mutated copy of the gene, and their daughter inherited one from each of them, so she developed the disease. There was a 25% chance that she would pass it on.
In these cases, the first two years of life are crucial. This is the window of opportunity to intervene and ensure that the child does not have a speech delay. After this time, the region of the brain dedicated to hearing, which does not receive any stimulation, tends to focus on another task, often vision. Until now, the usual treatment was a cochlear implant, a device that is installed in the inner ear and that alleviates hearing loss, but does not cure it.
When they were diagnosed, Abril’s father, Daniel Hernández, a 39-year-old salesman from Extremadura, started searching on the Internet. He discovered the results of a clinical trial in China in which several children who had been deaf since birth had regained their hearing, and even spoken, after receiving a new gene therapy treatment. When he found out that a similar trial was going to be opened in Spain, neither he nor his wife had any doubts.
“We knew we had to do it, even though we were scared, it was a unique opportunity,” recalled María Montaña, a 37-year-old technical architect from Extremadura, a few days ago in the otorhinolaryngology ward of the Clínica Universidad de Navarra (CUN), in Pamplona, while waiting for her daughter to come out of a hearing test.
The human ear is a marvel that we often overlook. Sound waves reach the ear, are amplified by several tiny bones, and penetrate into the inner ear, where there are a few milliliters of watery fluid called endolymph. Inside the cochlea, a spiral structure similar to a snail’s shell, there are thousands of hair cells that bathe in this fluid, collect the sound waves with their hairs, and transform them into chemical signals that they transmit to the first neurons. And at that moment the brain hears; all in fractions of a second.
Raquel Manriquean ENT specialist at the Navarre hospital, describes this process as a row of dominoes that fall one by one. In Abril’s case, there is a gap between each piece, so that the sound never reaches the brain. This gap is due to a mutation in the gene OTOF which prevents it from producing otoferlin, a protein essential for inner ear cells to communicate with the brain.
On May 2, doctors at the CUN sedated Abril to make a small incision behind her right ear. The goal was to reach the cochlea, smaller than the nail of the little finger, and introduce a catheter through which they injected the new gene therapy DB-OTO, developed by the American company Regeneron. The treatment contains the correct version of the gene packaged in harmless adenoviruses. These viruses enter the hair cells of the ear and release their genetic load, potentially restoring the ability to hear. Recovery is so fast that the patient leaves the hospital the next day.
Abril has been the first child in Spain to be treated in a clinical trial that is also being carried out in the United Kingdom and the United States, and which is evaluating the safety and effectiveness of this experimental therapy. In the United Kingdom, Opal, a deaf 18-month-old girl, has almost completely recovered her hearing. In the United States, in another similar trial, Aissam, a 12-year-old boy, was treated and has managed to recover his hearing, although he will probably not be able to learn to speak, as his doctors explained to EL PAÍS. China is leading the way with a very similar therapy that gave extraordinary results in six children at the end of last year.
Doctors have not yet detected any signs of hearing loss in April. This is not alarming because the first signs can come up to six months after the operation. “It is one thing that we are putting the missing domino piece in place, but now it has to start working and that takes time. But we are hopeful because the group from China Has published “We already have the results and we see good responses,” confesses Manrique.
His father, Manuel, is head of otorhinolaryngology at the Navarre hospital. “We are facing the first curative treatment for these types of deafness; until now, all procedures were palliative,” he says. The 66-year-old doctor, a pioneer of cochlear implants in Spain, believes that this is the first step towards a near future in which this and other congenital deafness can be reversed with gene therapy, without the need for another intervention.
The Pamplona hospital hopes to treat another four children aged one, eight, 10 and 16 within the trial. This Wednesday the first patient was also operated on at the Ramón y Cajal Hospital in Madrid, a two-year-old girl, explains Rubén Polo, an ENT specialist who heads this arm of the trial. And there is a thi
rd centre, the Materno-Infantil University Hospital in Las Palmas, in the Canary Islands, waiting for patients. “With this type of therapy, the sooner the intervention is carried out, the better recovery of hearing can be expected and, therefore, better development of the auditory cerebral cortex. If this has not developed, no matter how much hearing is recovered, language cannot develop,” he emphasises.
One of the key scientists in the development of these new therapies has been Ignacio del Castillo, a geneticist at Ramón y Cajal. Twenty years ago, the researcher began studying the different mutations of the OTOF that cause congenital deafness and to try to understand its frequency. Of all the congenital deafness, which affects two out of every thousand newborn children, mutations of the OTOF They account for 3%. Del Castillo has discovered several of them, especially one that originated in Spain and from there spread to Cuba, Argentina, Colombia, and probably other Latin American countries. This mutation affects about four newborns out of every 100,000, a frequency that is up to four times higher than in other countries.
Del Castillo has met an entire family from Cantabria who have been affected by this type of deafness for generations. “Imagine if some of these families have faith in science,” she explains over the phone, “that we have two 12-year-old girls who have resisted having cochlear implants placed in both ears, because they were hoping that one day gene therapy could cure at least one of them.” “These two girls are waiting to be treated and will probably benefit from it,” she stresses. Del Castillo believes that the recovery of hearing thresholds seen in China is “spectacular.” The only unknown, she warns, is how long the effects of the treatment last.
Jonathon WhittonRegeneron’s CEO, explains that for now all patients will receive treatment in one ear. If initial success is confirmed, and once the correct dose is adjusted, the second ear will be treated, provided that a cochlear implant has not been performed previously. “Our intention is to submit an application for approval at the end of next year,” explains this audiologist who has been involved in the project since 2016. At the same time, the company is already researching similar therapies against more common genetic deafness, such as the lack of the connexin protein.
Daniel, Abril’s father, knows that if everything goes well, his daughter won’t remember any of this. These days, he and his wife are so attentive to any changes that sometimes they think their daughter has heard them when they call her. But the doctors have told them that they won’t notice anything; it will be them first, with the tests that measure the electrical impulses that reach the brain, who will know that Abril can already hear. “Tomorrow we will tell her what has happened since her birth so that she will know. For now we are within the expected time frame and we have to be patient,” Daniel concludes.
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