PHILADELPHIA - Aissam Dam, an 11-year-old boy, grew up in a world of deep silence. He was born deaf and had never heard anything. While living in a poor community in Morocco, he expressed himself using a sign language he invented and had no education.
Last year, after he moved to Spain, his family took him to a hearing specialist, who made a surprising suggestion: Aissam could be eligible for a gene therapy clinical trial.
On October 4, Aissam was treated at the Children's Hospital of Philadelphia, becoming the first person to receive gene therapy for congenital deafness in the United States. The goal was to get him to hear, but the researchers had no idea if the treatment would work and, if so, how much he would hear.
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The treatment was a success and introduced a child who had known nothing about sound to a new world.
"There is no sound I don't like," Aissam said during an interview last week with the help of interpreters. "They are all good."
While hundreds of millions of people in the world live with hearing loss defined as disabling, Aissam is among those whose deafness is congenital. It is an extremely rare form, caused by a mutation in a single gene, otoferlin. Otoferlin deafness affects approximately 200,000 people worldwide.
The goal of the gene therapy is to replace the mutated otoferlin gene in patients' ears with a functional gene.
While it will be years before doctors enroll many more patients - and younger patients - to further test the therapy, researchers say success for patients like Aissam could lead to gene therapies that target other forms of congenital deafness.
It's a "groundbreaking" study, says Dr. Dylan K. Chan, pediatric otolaryngologist at the University of California, San Francisco, and director of the Children's Communication Center; he was not involved in the process.
The project in which Aissam participated is backed by Eli Lilly and a small biotechnology company it owns, Akouos. Researchers hope to eventually expand the study to six centers in the United States.
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The Aissam trial is one of five currently underway (the others are in China and Europe) or about to begin.
Researchers from all five studies will present their data on February 3 at a meeting of the Association for Research in Otolaryngology.
According to the researchers, the studies mark a new frontier for gene therapy, which until now had avoided 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 why so many researchers started using them. That form of congenital deafness is "low-hanging fruit," according to Dr. John A. Germiller, an otolaryngologist who leads the CHOP study.
The mutated otoferlin gene destroys a protein in the hair cells of the inner ear that is needed to transmit sound to the brain. In many of the other mutations that cause deafness, hair cells die during infancy or even in the fetal stage. But in otoferlin deafness, hair cells can survive for years, giving the defective gene time to be replaced with gene therapy.
There is a benefit to using gene therapy to help children hear. Most mutations that affect hearing - there are about 150 - do not affect any other part of the body. Some genes are actually unique to the ear.
The inner ear is a small closed compartment, so gene therapy delivered there won't affect cells in other parts of the body, says 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 cavity close to the center of the skull, is a challenge. The cochlea is filled with fluid, is lined with 3500 hair cells and is surrounded by a dense bone dome with a small, round membrane. Sound causes a wave of fluid in the cochlea and stimulates the hair cells to send signals to the brain. Each hair responds to a different frequency, allowing a person to hear the richness of sound.
The gene therapy consists of a harmless virus carrying new otoferlin genes in two drops of fluid that are gently injected along the length of the cochlea, delivering the genes to each hair cell.
But despite the promise of otoferlin gene therapy, it has been difficult to find the right patients for the trial.
One problem is the whole idea of treating deafness.
"There is an internal deaf community that doesn't see itself as someone who needs to be healed," says Dr. Robert C. Nutt, a developmental and behavioral pediatrician in Wilmington, North Carolina, who is deaf.
Some deaf parents, he added, celebrate when their newborn's hearing test shows that the baby is also deaf 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 the auditory nerves in the inner ear, allows patients to hear sounds, especially those needed to understand speech. But the implant does not provide the full richness of sound - and it is said to help with hearing, but without fully restoring it.
Most babies born with otoferlin deafness receive cochlear implants at a young age and are therefore not eligible for the trial. The implants slightly alter the cochlea, which could hinder the interpretation of gene therapy results.
The Food and Drug Administration, which authorized the CHOP study, asked for safety reasons that researchers 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 had otoferlin deafness and who did not have cochlear implants.
Aissam has never had cochlear implants. He never received any training in Morocco to help him develop communication skills. But three years ago, when he was eight, his father, Youssef Dam, a construction worker, got a job in Barcelona, Spain. For the first time, Aissam went to school and enrolled in a school for the deaf, where he learned Spanish Sign Language. Shortly afterwards, his family heard about the gene therapy trial.
When Aissam qualified to be 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 wasn't even clear what dose of the new genes should be given. All the researchers were concerned with were studies with mice. "We were flying blind," Germiller said.
Aissam's results were remarkable, according to his doctors. In an interview at CHOP, his father said through an interpreter - he speaks a North African language from the Amazigh family, commonly known as Berber - that Aissam heard traffic noises just days after treatment. When Aissam underwent a hearing test two months later, his hearing in the treated ear was almost normal.
But no matter how well the gene therapy works, the researchers acknowledge that Aissam may never be able to understand or speak a language, Germiller said. The brain has a narrow window for learning to speak, starting around age 2 to 3, he explained. After the age of 5, the window for learning spoken language is permanently closed.
Hearing can still help patients even if they never learn to speak, he noted. They can hear traffic or know when someone is trying to communicate. The ability to hear can also help with lip reading.
Now that gene therapy has proven safe for Aissam and another child in Taiwan who was treated two months after him, researchers at the Philadelphia hospital can move on to younger children. They have two in a row, a 3-year-old boy from Miami and a 3-year-old girl from San Francisco, both of whom received cochlear implants in only one ear so that the other could be treated with gene therapy.
If the Lilly trial of otoferlin gene therapy proves effective and safe, "there will be a lot of interest in other genes" that cause deafness, said Dr. Margaret A. Kenna, an otolaryngologist at Boston Children's Hospital and professor of otolaryngology. at Harvard Medical School.
Kenna, an investigator in the Lilly trial, added: "It took a long time."
"For decades, people have been saying, 'When is this going to work?'" Kenna said. "I didn't think that gene therapy would start during my practice life. But here it is."
Of the other studies, two are in China, where researchers are treating younger children and in both ears. Results of this, supported by the National Natural Science Foundation of China and Shanghai Refreshgene Therapeutics, will be reported on Wednesday in the journal The Lancet. The other is supported by Otovia Therapeutics and various programs in China.
A third study is sponsored by Regeneron and Decibel Therapeutics. Researchers in Europe have so far treated one child, under the age of two, in one ear. Another study by Sensorion is expected to start 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 remarkable 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 team had a certified deaf interpreter - a deaf person 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 robbed the conversation of spontaneity and forced Aissam to answer in short sentences, minimizing the expression of his personality.
But Aissam managed to convey the miracle of hearing.
Noises and voices initially scared him, he said. But when the world of sound opened up, he began to enjoy every sound he heard: elevators, voices, the sound of scissors cutting his hair in a barbershop.
And there was music, which he heard for the first time one day while getting his hair cut.
When asked if there was a sound he particularly liked, Aissam didn't hesitate.
"People," he signed.
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