Excitement Around Gene Therapy for Hearing Restoration

Hinrich Staecker, MD, PhD, the David and Mary Zamierowsky Endowed Professor in the department of otolaryngology at the University of Kansas School of Medicine, suggested that “the excitement around gene therapy is that it has the potential to truly cure a hearing loss rather than using a prosthetic device.”

Cochlear implants have transformed the landscape of hearing rehabilitation, but hearing with a cochlear implant is not perfect, “and the sound quality does not match natural hearing,” Dr. Lustig said. Gene therapy “has the potential to restore natural hearing without the downsides of a cochlear implant.”

For Dr. Choo, the most salient benefit of gene therapy versus current best practices is “the restoration of native hearing that reduces or eliminates the need for hearing appliances in order to hear and function.” He explained, “Native hearing, as compared to hearing aids or implants, takes advantage of all the acoustic benefits of human ear anatomy and physiology.”

Risks and Challenges

Along with potential benefits, several risks and challenges are associated with gene therapy for hearing loss.

“Most importantly, there is a risk that the gene therapy will not work, that is, not improve an individual child’s hearing. Gene therapy is experimental, and we don’t know how well each individual will respond, or not respond,” explained Dr. Germiller. Additionally, there is the risk of injury to the interior of the inner ear, “from either the physical injection process, or the gene therapy agent, which is generally a virus. Such injury could affect the hearing result, and it could cause scarring or other effects that could make it more difficult to perform a cochlear implant in the future. Finally, there is a risk of injury to the vestibular system, which could cause dizziness and balance problems.”

According to Dr. Lee, the main known risk factors include “an immune response from the introduction of foreign material (the therapeutic gene and/or viral vector) as well as potential effects from introducing genetic material to surrounding cells in the tissue adjacent to the intended target cells. In addition, there may be other unknown effects that result from further mutations due to the insertion of rescue genes into the patient’s DNA. Furthermore, as gene therapy is still very early in development, we do not have a clear understanding of potential long-term consequences.”

Researchers face uncertainty about the durability of the improvements after gene therapy. They are also challenged by the costs of developing the therapies and running the clinical trials, along with the task of finding patients and completing genetic testing for rare forms of genetic deafness.

More than 150 genes are associated with non-syndromic hearing loss, of which some affect only a small fraction of patients with hearing loss, Dr. Taiber explained, adding that manufacturing the AAV vector “at scale with clinical-grade standards presents significant technical complications.”

For OTOF-related hearing loss, the incidence is approximately 1% of cases of genetic hearing loss, Dr. Lustig said. “The most common form of genetic deafness is connexin-related hearing loss, but animal models for this form of hearing loss are not ideal to test out therapies.”

Patient and Ethical Considerations

Gene therapy is ideal only for patients with a monogenic etiology of genetic hearing loss, meaning the loss is due to the mutation of a single gene, explained Dr. Lee. “In the case of polygenic etiologies, replacing only one of multiple defective genes will not restore normal hearing.”

Many forms of genetic hearing loss are recessive, so they may be amenable to the gene replacement strategy. “However, the autosomal dominant losses (DFNA genes) may need different approaches, such as gene inactivation or gene editing,” Dr. Germiller explained. “These are newer approaches now being developed for many other conditions, and which may show promise for some forms of genetic hearing loss.”

Appropriate timing of gene therapy delivery is another significant challenge, according to Dr. Choo. “In the case of OTOF gene therapy, the well-maintained cochlear cytoarchitecture in auditory neuropathy allows OTOF to be replaced into an otherwise healthy cochlea even years after birth; however, other forms of genetic hearing loss disrupt cochlear/inner ear homeostasis such that hair cells, supporting cells, and stria vascular cells, etc., all begin to die off either at birth or even before birth. At that stage, restoring a missing gene would be unlikely to result in those cells coming back or regenerating, and in turn, hearing would not be recovered. This type of thought process and research has led to considerations of delivering some potential gene therapies in utero before cell degeneration and irreversible damage occur.”

For OTOF-related hearing loss, along with genetic testing to verify the presence of the defective gene, audiometric testing is required to document auditory neuropathy that would be consistent with OTOF-related hearing loss,” Dr. Lustig explained. There are no genetic markers that make a patient more likely to benefit from gene therapy, but “for OTOF-related deafness, we want to see intact otoacoustic emissions.”

“All of the patients in the gene therapy trials are children or adolescents with varying degrees of hearing loss. Improvements in language seem to track what we see for cochlear implants. Parents are excited about these results,” Dr. Lustig continued. “As all of the patients receiving OTOF gene therapy are part of a clinical trial, they will be required to have regular follow-ups to monitor hearing, language development, and other medical issues that may arise.”

For all hearing loss gene therapy trials worldwide, the treatment is introduced via otologic surgery. Follow-up care and post-operative visits are “similar to that for patients undergoing a transcanal middle ear exploration with stapedotomy or undergoing a cochlear implant procedure,” Dr. Germiller said. “In the various current trials, timing of the first hearing evaluation varies, but is typically between four and six weeks post-operatively; then subsequent testing is typically performed repeatedly for several years after that.”

Dr. Choo highlighted that patient safety remains the priority in these first-in-human gene therapy trials for deafness. Sufficient clinical trials that monitor for both short-term and long-term effects are needed “to determine how broadly and in what conditions and what patients these treatments can be applied.”

Notably, “these are the very first trials for deafness and the first involving direct injection of the gene therapy into the cochlea of patients,” Dr. Choo said. “Much more work and follow-up are needed despite the excitement and incredible promise shown from these early cases.”

Some individuals are uncomfortable with gene therapy, as it involves using a virus to deliver the normal gene back into humans, Dr. Lustig explained. “There are others who are against doing anything that might interfere with someone’s natural genetic background,” he said. “As with cochlear implantation, the Deaf community may be very uncomfortable with any therapy that treats hearing loss as a disease.”

However, “most regulatory bodies are now comfortable with gene therapy as long as the appropriate safeguards are addressed,” Dr. Lustig added.

Future Developments

Dr. Lustig suggested that, along with the continuation of the OTOF gene therapy trials, other gene therapy treatments for genetic hearing loss will likely enter clinical trials over the next decade. “Gene therapy for hair cell regeneration needs more work until it is ready for prime time,” he added.

The next steps in research and development for gene therapy to treat hearing loss include “identifying additional forms of genetic deafness amenable to gene therapy and identifying all the necessary growth factors and proteins that impact hair cell development.” Dr. Lustig suggested that “this would allow both hair cell regeneration and synaptogenesis.”

Looking ahead, Dr. Staecker said, “These early-stage trials will move us towards better classification of hearing loss patients. Several more trials for different genetic hearing losses should be available in the next five to 10 years, with approved therapies rolling out during the next three to 15 years.”

According to Dr. Taiber, within 10 years, at least several genes will have FDA or European Medicines Agency approval for gene therapy, making “comprehensive genetic testing a crucial step in the diagnostic workup of children with hearing loss. I hope that novel technologies will emerge to surpass or complement AAV, providing treatment options for cases that cannot be addressed by AAV-based approaches.”

The auditory neuropathy population is a relatively small subset of patients with sensorineural hearing loss, said Dr. Choo. “As other genetic treatments begin coming online for more common causes of genetic hearing loss, the impact of work in this field will become much more striking.”

“Notably, the current techniques for delivering gene therapies remain very surgical. As a result, otolaryngologists will inevitably be part of the clinical and scientific teams that develop and spread gene therapies for deafness as this modality matures and expands. Otolaryngology’s continual efforts to refine our techniques to more minimally invasive and atraumatic methods align perfectly with the needs for future gene therapeutics,” Dr. Choo said.

“Advances in other technologies adopted in otolaryngology, such as robotic-assisted surgery, will likely intersect with gene delivery in some cases and further enhance outcomes,” Dr. Choo said. “Hybridization of technologies, such as cochlear implantation with the addition of biologicals to enhance cochlear implant function, may also be intermediary steps as we continually advance our understanding of the molecular biology of hearing and deafness while also perpetually improving implant technologies.”

Dr. Lee first heard about the idea of gene therapy for hearing loss when he was a medical student around 30 years ago. “It’s amazing the progress we have made in the past decade,” he said. “I anticipate rapid advancement in the decade to come, and we may have gene therapy as a well-accepted option for treatment for hearing loss before I retire.”     

Katie Robinson is a freelance medical writer based in New York.