Gene therapy has had a number of success stories with regards to treating blood disorders like hemophilia and beta-thalassemia, as well as in cancer research. Now, the latest breakthrough in gene therapy has been in restoring hearing loss in an 11-year-old boy.
A team of scientists at the Children’s Hospital of Philadelphia (CHOP) was able to treat the child with the first-ever gene therapy for genetic hearing loss in the U.S.
“Gene therapy for hearing loss is something that we physicians and scientists in the world of hearing loss have been working toward for over 20 years, and it is finally here,” said John A. Germiller, Associate Professor at Perelman School of Medicine at the University of Pennsylvania, in a press release.
The 11-year-old, who was born deaf and was living in a poor community in Morocco until last year when he moved to Spain with his family, was eligible for the study because his hearing loss was caused by OTOF mutations. This accounts for 2% to 8% of cases of congenital deafness, according to a Reuters report.
The OTOF gene encodes for the protein otoferlin, and mutations of the gene are associated with profound hearing loss, as well as another type of hearing loss called auditory neuropathy, where the ear detects sounds but has trouble sending the signals to the brain. It is one out of more than 150 genes that are linked to hearing loss. One in 500 newborns is affected by genetic hearing loss globally.
How does gene therapy treat hearing loss?
As part of the trial, the child underwent surgery at the hospital where the gene therapy was placed into the inner ear using an endoscope. An ear endoscope allows doctors to perform operations in the middle and inner ear without being as invasive as making an incision behind the ear.
The AK-OTOF gene therapy contains copies of the normal OTOF gene, which was delivered to the ear. The normal, non-mutated OTOF genes allow sensory cells to function, by activating the auditory nerve to send impulses to the brain, which then decodes it as the sound we recognize. But you cannot simply put these genes into the ear.
The genes are encased in a viral vector, which is essentially a harmless virus that transports the genes to hair cells in the inner ear. Hair cells are sensory receptors, meaning that they detect the sound for it to be converted to electrical signals. Two drops of the vector containing the genes were injected into the patient’s ear.
Four months after receiving the therapy, the child can now hear his parent’s voice and the sound of music. His condition has improved from severe, to mild to moderate hearing loss in the one ear that he was treated for.
“While the gene therapy we performed in our patient was to correct an abnormality in one, very rare gene, these studies may open the door for future use for some of the over 150 other genes that cause childhood hearing loss,” said Germiller.
AK-OTOF was greenlit for the Orphan Drug Designation by the U.S. Food and Drug Administration (FDA), and the European Commission in 2021 and 2022. At present, the clinical trial is funded by precision genetic medicine company Akouos, which belongs to pharma giant Eli Lilly. The results of the ongoing trial will be presented at the 2024 Association for Research in Otolaryngology (ARO) in California, this Saturday.
Harvard study solves gene therapy concern
Coincidentally, encouraging results from another trial were brought to light last week. The study co-led by Harvard Medical School (HMS), treated six children aged one to seven, with hereditary hearing loss caused by an OTOF gene mutation. It was held at Fudan University in China, where the children received a gene therapy that helped manufacture the missing otoferlin protein, a similar mechanism to that of AK-OTOF. However, at first, researchers encountered a significant problem. The OTOF gene wouldn’t fit into the virus.
But they soon bypassed the issue by cutting up the gene, and inserting the two halves into separate viruses. Both were then injected into the cochlea. This did not seem to pose a problem as the therapy continued to assemble the protein, which could allow hair cells to transmit signals to the brain.
Five of the young participants responded to the therapy, and were able to recognize speech. In fact, some of the parents noticed that their children’s hearing was improving even before the researchers did. When one of the parents called out to her daughter, the child turned towards her.
With hopes of bagging the approval of U.S. regulators in the next three to five years, Zheng-Yi Chen, co-senior author of the study believes that this “opens the door to developing other treatments for different kinds of genetic deafness.”
“This is truly remarkable. When we tell the story, even for our colleagues, it brings a tear to the eye,” said Chen, associate professor of otolaryngology at HMS, in The Harvard Gazette. “I’ve been working in this field for three decades, and I know how difficult it has been to come to this point. I also know we’re at the juncture of a great future.”
The trial is supported by Shanghai Refreshgene Therapeutics, and researchers will present their findings at the otolaryngology meeting in California on Saturday.
Success in gene therapy for hearing loss trials grows
As gene therapy seems to be the buzz these days, these are just two of five ongoing gene therapy trials for hearing loss garnering attention this year. Another one using adeno-associated viruses (AAV)-mediated gene therapy is also being conducted in China. Two patients, aged five and eight, showed improvement in hearing. Both of them could recognize speech after treatment, according to the study sponsored by Otovia Therapeutics.
Meanwhile, a European study run by Regeneron is investigating DB-OTO, yet another otoferlin gene therapy. Initial results published back in October, revealed that the first child who received the treatment experienced improvements in hearing in six weeks, according to an auditory brainstem response (ABR). An ABR is a test to check how well the nerves and the brain respond to sound, and in the case of OTOF gene-mutated hearing loss, it is typically absent.
Another team that is set to present at the otolaryngology summit this weekend is Sensorion. The French biotech will soon begin a phase 1/2 study where it will test the efficacy of its candidate SENS-501 in young children. While it aims to evaluate the safety of the therapy in the dose escalation cohort, ABR will be the primary endpoint in the dose expansion cohort.
However, like with the HMS therapy, other researchers will have to tackle the problem of getting the virus to envelope the gene that is huger than itself. Moreover, it isn’t easy to transfer genes into the cochlea, a region in the ear that is very close to the center of the skull. This is partly because the inner ear is cut off from general circulation by a blood–cochlea barrier, which is similar to the blood-brain barrier. This makes delivery harder but, at the same time, more efficient as it is a closed space, and so, a smaller dose will suffice when compared to systemic delivery.
As hearing loss research moves forward, more and more biotechs committed to curing hearing loss are sprouting up. And with other therapies like stem cell therapy potentially on the horizon to treat hearing loss, the development of gene therapy to address the genetic disorder contributes to an abundance of ongoing success in research.
New technologies related to gene therapy for hearing loss:
- Antisense Oligonucleotides DFNA9 – Radbound University
- Antisense Oligonucleotides (ASO) as a Therapeutic for Usher Syndrome – Rosalind Franklin University