by PHILADELPHIA — Aissam Dam, an 11-year-old boy, grew up in a world where there was a lot of silence. He was born deaf and could not hear anything. While living in a poor community in Morocco, he expressed himself with a sign language he created and had no schooling.
Last year, after moving to Spain, his family took him to a hearing specialist, who made a surprising suggestion: Aissam might be eligible for a clinical trial using gene therapy.
On October 4, Aissam was treated at the Children’s Hospital of Philadelphia, becoming the first person in the United States to receive gene therapy for congenital deafness. The goal was to provide him with hearing, but the researchers had no idea if the treatment would work or, if it did, how much he would hear.
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The treatment was successful, sending a child who had never heard of a sound into a new life.
“There is no sound that I don’t like,” said Aissam, with the help of interpreters during an interview last week. “They are good.”
Although hundreds of millions of people in the world live with hearing loss which is defined as a disability, Aissam is among those who are born deaf. It is a very rare form caused by a mutation in one gene, otoferlin. Otoferlin deafness affects about 200,000 people worldwide.
The goal of gene therapy is to replace the mutated otoferlin gene in patients’ ears with a functional gene.
Although it will take years for doctors to sign up many more patients — and younger ones — to further test the therapy, the researchers said success in patients like Aissam could lead to gene therapies that target other forms. congenitally deaf.
It is a brand new study, said Dr. Dylan K. Chan, a pediatric otolaryngologist at the University of California, San Francisco, and director of its Children’s Communication Center; he was not involved in the trial.
The one Aissam participated in is backed by Eli Lilly and a small biotech firm he owns, Akouos. Investigators hope to eventually expand the study to six centers across the United States.
The Aissam trial is one of five ongoing (the others are in China and Europe) or about to begin.
Investigators from each of the five studies will be presenting their data on February 3 at a meeting of the Society for Research in Otolaryngology.
The studies, the researchers said, represent a new frontier for gene therapy that, until now, had eluded hearing loss.
“There has never been a biological, medical or surgical way to correct the underlying biological changes that cause the inner ear to malfunction,” Chan said.
Although otoferlin mutations are not the most common cause of congenital deafness, there is a reason that so many researchers have started with it. That type of congenital deafness is “low-hanging fruit,” said Dr. John A. Germiller, an otolaryngologist who is leading the CHOP study.
The mutated otoferlin gene destroys a protein in the hair cells of the inner ear that is necessary to transmit sound to the brain. With many of the other mutations that cause deafness, hair cells die during childhood or even in the fetal stage. But with otoferlin deafness, hair cells can live for years, making it possible to replace the faulty gene with gene therapy.
There is an advantage to using gene therapy to make children able to hear. Most of the mutations that affect hearing – there are about 150 – do not affect any other part of the body. Some genes are unique to the ear.
The inner ear is a small, closed compartment, so gene therapy delivered there would not affect cells in other parts of the body, said Manny Simons, CEO and co-founder of Akouos and senior vice president of gene therapy at Lilly.
But getting the genes to the cochlea, a spiral-shaped cavity near the center of the skull, is challenging. The cochlea is filled with fluid, is lined with 3,500 hair cells and is covered in a dense dome of bone with a tiny round membrane. A sound wave sends fluid out into the cochlea and stimulates the hair cells to transmit signals to the brain. Each hair responds with a different frequency, enabling one to hear the richness of the sound.
The gene therapy consists of a harmless virus carrying new otoferlin genes in two drops of liquid that is gently injected down the length of the scalp, delivering the genes to every hair cell.
But despite the promise of otoferlin gene therapy, it has been difficult to find the right patients for the trial.
One issue is the idea of treating deafness.
“There is an internal Deaf community that doesn’t see the need for a cure,” said Dr. Robert C. Nutt, a developmental and behavioral pediatrician in Wilmington, North Carolina, who is deaf.
He also said that some Deaf parents celebrate when their newborn child’s hearing test reveals that the child is deaf, too, and can therefore be part of their community.
Further complicating the issue of gene therapy is the standard intervention for otoferlin hearing loss: a cochlear implant. The device, which uses electrodes to stimulate auditory nerves in the inner ear, allows patients to hear sounds, especially those needed to understand speech. But the implant doesn’t provide the full richness of sound – and is said to help but not completely restore hearing.
Most children born with otoferlin deafness receive a cochlear implant as infants and are therefore not eligible for the trial. The implants change the cochlea slightly, which can hinder the interpretation of gene therapy results.
The Food and Drug Administration, which allowed the CHOP study to proceed, requested that the researchers, for safety reasons, start with older children, not infants, and treat only one ear.
The challenge for the US study was to find older children whose parents would agree to the study, who were otoferlin deaf and did not have cochlear implants.
Aissam has never had cochlear implants. He never received schooling in Morocco to help him develop communication skills. But three years ago, when he was 8, his father, Youssef Dam, a construction worker, got a job in Barcelona, Spain. For the first time, Aissam went to school, enrolling in a school for the deaf, where he learned Spanish Sign Language. Soon after, his family learned about the gene therapy trial.
When Aissam was deemed eligible as patient No. 1, Lilly and Akouos paid for him and his father to live in Philadelphia for four months, while Aissam received gene therapy and follow-up hearing tests.
No one knew whether the nerve cells that communicate with the hair cells of the cochlea would still be intact and functional in someone who had been deaf for 11 years, Simons said.
It was not even clear what dose of the new genes to give. The researchers only had to proceed with studies with mice. “We were flying blind,” Germiller said.
Aissam’s results, his doctors said, were amazing. In an interview with CHOP, his father said through an interpreter – he speaks a North African language from the Amazigh family, commonly known as Berber – that Aissam was hearing traffic noise just days after the treatment. When Aissam had a hearing test two months later, his hearing in the treated ear was close to normal.
But no matter how well the gene therapy works, the researchers recognize that Aissam may not be able to understand or speak language, Germiller said. The brain has a narrow window to learn to speak starting around age 2 to 3, he explained. After the age of 5, the window to learn a spoken language is permanently closed.
Listening can still help patients even if they don’t learn to speak, he noted. They can hear traffic or know when someone is trying to communicate. The ability to listen also helps in lip reading.
Now that gene therapy is safe for Aissam and another child in Taiwan who was treated two months later, researchers at the Philadelphia hospital are able to move on to younger children. Two of them, a 3-year-old boy from Miami and a 3-year-old girl from San Francisco, both received a cochlear implant in one ear, so that the other could be treated with gene therapy.
If Lilly’s trial of otoferlin gene therapy proves to be effective and safe, “there will be a lot of interest in other genes” that cause deafness, Dr. Margaret A. Kenna, otolaryngologist at Children’s Hospital in Boston and professor of otolaryngology. at Harvard Medical School.
Kenna, an investigator in Lilly’s trial, said, “It’s been a long time coming.”
“For years people have been saying, ‘When is this going to work?'” Kenna said. “I never thought that gene therapy would be introduced during my practice. But this is it.”
Of the other studies, two are in China where investigators are treating younger children and in both ears. Results from one, supported by the National Natural Science Foundation of China and Shanghai Refreshgene Therapeutics, will be reported Wednesday in the journal The Lancet. The other is supported by Otovia Therapeutics and various programs in China.
The third study is sponsored by Regeneron and Decibel Therapeutics. Researchers in Europe have so far treated one child, younger than 2, and in one ear. Another study at Sensorion is expected to begin this month.
On a recent frigid morning, Aissam sat in a conference room at CHOP and, with the help of three translators, patiently answered questions about his amazing experience. He is a solemn child with a round face and big brown eyes. There was an interpreter for his father, and the sign language staff had a Certified Deaf Interpreter — a deaf person who translated his signs into American Sign Language — and an interpreter who knew American Sign Language and spoke his words.
Their system worked to some extent but they robbed the conversation of spontaneity and forced Aissam to respond in sentences or short phrases, reducing the expression of his personality.
But Aissam managed to express the surprise of the hearing.
Noises and voices frightened him at first, he said. But then, as the world of sound opened up, he began to enjoy every sound he heard – elevators, voices, the sound of scissors cutting his hair at a barber shop.
And there was music, which he heard for the first time one day while cutting his hair.
When asked if there was a sound he particularly liked, Aissam did not hesitate.
“People,” he signed.
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