“The most striking example of advancements in gene therapy was presented at the 2024 Association for Research in Otolaryngology (ARO) MidWinter Meeting,” said Dr. Choo. Researchers from the Children’s Hospital of Philadelphia (CHOP)—one of the Akouos study sites—presented their initial treatment of an 11-year-old patient with auditory neuropathy who underwent otoferlin gene therapy. “That patient had an astounding recovery of his hearing following a single injection of the adenovirus-mediated OTOF delivery to his cochlea. While this first gene therapy for deafness addressed a very specific subset of patients with sensorineural hearing loss, it clearly provided the proof of principle that the concept of complex gene replacement therapy is feasible for human deafness,” Dr. Choo said.
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June 2025Gene Replacement
Dr. Lustig explained that gene therapy for hearing loss works either by altering the developmental pathways for hair cell growth—i.e., trying to regrow hair cells or driving neurons to existing hair cells in the case of acquired deafness, such as through noise trauma or age-related hearing loss—or by replacing the function of a defective gene product so normal function will be restored in the case of genetic deafness.
John Germiller, MD, PhD, an attending surgeon and director of clinical research in the division of otolaryngology at CHOP, and associate professor of clinical otolaryngology–head and neck surgery at the University of Pennsylvania, said that most of the gene therapy trials underway around the world, for hearing loss and other conditions, use gene replacement, also known as gene augmentation.
In this approach, a nonfunctioning gene is replaced in a target cell to restore expression of that gene and thus mitigate the disease. “Most in vivo gene therapy approaches package the replacement gene into a viral vector, usually adeno-associated virus (AAV). The virus inserts the gene construct into the target cell, where it transits the cytoplasm and enters the nucleus,” Dr. Germiller said. “The DNA construct becomes an episome, which is a stable, circular DNA molecule that can last for many years. The replaced gene is then expressed from this episome, under control of one of various promoters. These promoters are attached just proximal to the gene of interest in the gene therapy DNA construct.”
Patients with an auditory neuropathy form of sensorineural hearing loss caused by mutation of the otoferlin gene lack any functional copies of this critical gene needed for the cochlear inner hair cells to function, Dr. Choo explained. “Somewhat uniquely in this clinical condition, the structure and other cells of the cochlea typically remain intact despite the absence of the otoferlin gene. As a result, replacing the missing gene back into an otherwise viable and functional cochlea is an ideal first candidate for gene therapy.”
“At a molecular/cellular level, the otoferlin gene encodes for a transmembrane protein that facilitates exocytosis of presynaptic vesicles—via a calcium-sensitive mechanism—at the inner hair cells. Without otoferlin, the inner hair cells are unable to transmit a signal across the synapse to the cochlear nerve,” Dr. Choo said.
Clinical trials are focused on OTOF-associated hearing loss, but researchers have identified several other genes as appealing next targets.
Shahar Taiber, MD, PhD, resident at the department of otolaryngology/head, neck and maxillofacial surgery in Tel Aviv Sourasky Medical Center in Israel, explained that additional preclinical work has shown promising results in animal models for TMC1, USH1C, SYNE4, STRC, and other genes associated with hearing loss.
Potential Benefits
Dr. Taiber, who is also a research fellow at the lab of Professor Karen B. Avraham in the department of human molecular genetics and biochemistry at Tel Aviv University, noted that “cochlear implants work by bypassing the hair cells in the cochlea and directly stimulating the spiral ganglion neurons, whereas current gene therapy strategies replace the defective gene, thereby ‘repairing’ the hair cells. This approach can potentially result in superior hearing sensitivity, dynamic range, and frequency resolution.
“Additionally, gene therapy eliminates the need for an external device that requires charging, may break, or present other maintenance challenges,” Dr. Taiber added.
The excitement around gene therapy is that it has the potential to truly cure a hearing loss rather than using a prosthetic device. — Hinrich Staecker, MD, PhD
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