NEW YORK – A patient suffering from a rare, genetic form of deafness can now hear after receiving an experimental gene therapy at the Children's Hospital of Philadelphia.
The 11-year-old patient, who was born deaf in both ears due to a mutation in the OTOF gene, is the first patient to receive a gene therapy for hereditary hearing loss in the US, according to CHOP. Based on initial results CHOP shared this week, the gene therapy has had a positive effect and led to an improvement in the child's hearing.
CHOP is the first clinical trial site in the US to administer the gene therapy, AK-OTOF, a potential treatment for hearing loss specifically associated with mutations in that gene. The treatment is being developed by Eli Lilly subsidiary Akouos and studied in a Phase I/II trial called the AK-OTOF-101 Study.
The University of Iowa is also an active clinical trial site in the US, a Lilly spokesperson said, and the company is planning for additional sites. Lilly is preparing to present positive early results from this Phase I/II trial, including data from a second patient, at the Association for Research in Otolaryngology's 2024 MidWinter Meeting in Anaheim, California, next month.
At CHOP, the 11-year-old patient underwent a surgical procedure to administer the investigational gene therapy in October. The adeno-associated viral vector-based gene therapy is designed to deliver a functional copy of the OTOF gene to cells in the cochlea, a part of the inner ear, so that cells are able to produce otoferlin, a protein that's critical for transmitting signals to the auditory nerve.
"The gene therapy study for congenital deafness due to otoferlin mutations represents an ongoing revolution in medicine to design customized drugs specifically for individuals with one of 7,000 rare diseases," Barry Byrne, director of the Powell Gene Therapy Center and associate chair of pediatrics at the University of Florida, told Precision Medicine Online. "Gene therapy for sensory problems like hearing or vision is especially rewarding [as they] impact the lives of patients in such a profound way."
Investigators observed the gene therapy's efficacy quickly in the trial, with the first patient experiencing restored hearing within 30 days of treatment, Lilly said in a statement this week. In the four months since the gene therapy was administered, the child's hearing loss is now at a "mild to moderate" level, according to CHOP — an improvement from before the treatment.
"It is a milestone worthy of celebration every time a gene therapy has first-time success treating human patients," said American Society of Gene & Cell Therapy CEO David Barrett, noting that while Phase Ia of the trial was open to patients ages 7 to 17 years old, enrollment is expanding to children as young as 2 years old in the Phase Ib portion of the study. "We're heartened to hear that the trial has been expanded to include 2- and 3-year-olds and hope to see similar success for all patients enrolled."
In the initial part of this open-label, dose-escalation Phase I/II trial, investigators are evaluating the safety and tolerability of a single dose of AK-OTOF administered to just one ear by monitoring adverse events. Investigators will also track changes from baseline in patients' auditory brainstem response.
Promising results from gene therapy trials of hearing loss caused by OTOF mutations suggest that gene therapy could be a viable avenue for treating other hereditary hearing loss problems, according to John Germiller, an attending surgeon and director of clinical research in the otolaryngology division at CHOP and an associate professor at Perelman School of Medicine at the University of Pennsylvania, who treated the 11-year-old patient. The AK-OTOF-101 Study, for example, is also evaluating the safety and performance of a device used to deliver AK-OTOF to the inner ear.
"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," Germiller, a principal investigator on the AK-OTOF-101 Study, said in a statement.
AK-OTOF, which has received orphan drug designation and rare pediatric disease designation from the US Food and Drug Administration, is just one of a growing number of gene therapies targeting OTOF-related hearing loss being studied in the US and abroad. Internationally, Lilly is also studying AK-OTOF as part of its Phase I/II trial at the National Taiwan University Hospital.
Sensorion last week announced plans to launch a Phase I/II trial of its gene therapy candidate targeting the condition, SENS-501, in France. Decibel Therapeutics, which has been acquired by Regeneron Pharmaceuticals, is testing its lead gene therapy candidate, DB-OTO, in a Phase I/II study in this setting. And Wednesday evening, The Lancet published a paper about a gene therapy being developed by the Eye & ENT Hospital of Fudan University and Refreshgene Therapeutics in Shanghai that restored hearing in five of six children who received it in China.