Gene Therapy: What lies ahead for treatment of hearing loss?

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Andrea Warner-Czyz PhD, Associate Professor
University of Texas at Dallas Callier Center for Communication Disorders

Scientists have worked on gene therapy for hearing loss for decades, but global interest has piqued in the past six months due to the publication of results from clinical trials around the world. No doubt, you have received links from family and friends about children for whom gene therapy has restored their hearing. For example, the Children’s Hospital of Philadelphia announced in January 2024 initial results for a child born with profound level of hearing in both ears whose hearing improved to mild-moderate levels after receiving investigational gene therapy. The latest viral story features Opal Sandy, a toddler diagnosed with auditory neuropathy in the United Kingdom, who received gene therapy before her first birthday and now has near-normal hearing in her treated ear, just six months later. Although the American Cochlear Implant Alliance focuses on implantable auditory technology, our mission supports the provision of comprehensive information on evolving options to improve communication and quality of life in children and adults who are deaf and hard of hearing. As clinicians and researchers, we need to educate ourselves as to the role of gene therapy as a treatment option for individuals who are deaf and hard of hearing – who is a candidate, how does it work, what do outcomes suggest, and which variables we still need to examine – and our role in guiding patient queries in this new landscape.

Who is a candidate for gene therapy?

First, we should know which patients who are deaf and hard of hearing qualify for gene therapy. Current clinical trials focus on children born with bilateral severe to profound levels of hearing related to nonsyndromic auditory neuropathy spectrum disorder (DFNB9), a rare condition that constitutes 1 to 10% of those with hearing loss (Vignesh et al., 2016). Auditory neuropathy spectrum disorder has heterogeneous etiologies (e.g., defect in the inner hair cells, pre- or post-synapse between the inner hair cells and the spiral ganglion neurons, or demyelination or axonal loss in the auditory nerve). Current candidates for gene therapy must have two non-functioning copies of the OTOF gene, which encodes otoferlin – a calcium sensory protein that underlies transmission of sound information between the inner hair cells and the afferent fibers of the spiral ganglion cells of the auditory nerve. Despite not having the otoferlin protein, the rest of the inner ear functions normally (i.e., functional outer hair cells and spiral ganglion neurons). Inclusion criteria for gene therapy clinical trials also often specify presence of otoacoustic emissions and/or the cochlear microphonic paired with absent or abnormal auditory brainstem response in at least one ear (that does not have a cochlear implant).

What is the goal of the therapy for the OTOF gene now in clinical trials?

The goal of gene therapy is to introduce a healthy copy of the OTOF gene to the cochlea to allow the inner hair cells to regain the function of the otoferlin protein, thereby restoring afferent synapses affording transmission of neural information from the cochlea to the primary auditory neurons in the spiral ganglion. Although the companies pioneering this gene therapy differ in many ways (e.g., surgical approaches, viral particles), they all involve gene replacement with a functional copy of the OTOF gene encased in a modified non-disease-causing virus (e.g., adeno-associated viral vector, or AAV). Injecting dual AAV vectors directly into the fluid-filled cochlea via the round window membrane yields the most efficient delivery to the inner ear (Landegger et al., 2017). Multiple pre-clinical studies using otoferlin knockout mice demonstrate recovery of hearing using AAV vectors to deliver the OTOF gene to the cochlea.

What clinical trials are underway? What are the outcomes thus far?

To date, four teams (presented in alphabetical order)--Akouos, Fudan University, Regeneron, and Southeast University/Otovia Therapeutics—have developed otoferlin-based gene therapy and reported on five clinical trials in a total of seventeen children (Lv et al., 2024; Qi et al., 2024). Chronologic age at study enrollment ranged from 10 months to 11 years with results reported between 1 and 6 months post-injection of a single dose. Most of the clinical trials administer the OTOF-based gene therapy to one ear, although two clinical trials implemented bilateral gene therapy in six children. Overall, 16 of 17 children exhibited recovery of hearing as evidenced from changes in pure-tone or auditory brainstem response thresholds from profound levels (>95 dB) to mild-moderate levels (e.g., 30-58 dB) or, in a few cases, severe levels (~80 dB). Most children showed improved auditory skill development, with some able to repeat words or localize sounds. No studies reported serious adverse events related to gene therapy.

Results from the clinical trials seem promising overall, with more than 90% of children with auditory neuropathy in the OTOF-based gene therapy clinical trials showing improved auditory skills post-treatment. However, the results also highlight the variability in outcomes from partial to full recovery of hearing – a sentiment shared by bioethicist Dr. Teresa Blankmeyer Burke in a webinar sponsored by Gallaudet University. She recognized that gene therapy may change hearing status to become medically hard of hearing, but it is not a cure. That is, children who receive gene therapy will still need to prioritize support for optimal auditory access aiding development of language, speech, and psychosocial skills.

The field still has many unanswered questions relative to gene therapy as a treatment for profound levels of hearing. Which factors serve as risk or protective factors for this treatment? Does implementation within a certain age range yield the best chance at restoration of hearing? Will children maintain improved hearing or will they require redosing, if possible, in the future? Will gene therapy increase vulnerability to damage from excessive noise, ototoxic agents, or aging? How will this work focused on OTOF apply to other genes identified for hearing loss?  Much is still unknown about how gene therapy will impact treatment of hearing loss.

At the same time, the hearing healthcare field has made important gains in understanding the underpinnings of hearing loss and strategies to address these issues at the level of the gene. We still have quite a bit of work ahead to address over 150 genes identified for hearing loss.

References

Landegger LD, Pan B, Askew C., Wassmer SJ, Gluck SD, Galvin A, Taylor R, Forge A, Stankovic KM, Holt JR, & Vandenberghe LH (2017). A synthetic AAV vector enables safe and efficient gene transfer to the mammalian inner ear. Nature Biotechnology, 35(3), 280-284. doi:10.1038/nbt.3781

Lv J, Wang H, Cheng X, Chen Y, Wang D, Zhang L, Cao Q, Tang H, Hu S, Gao K, Xun M, Wang J, Wang Z, Zhu B, Cui C, Gao Z, Guo L, Yu S, Jiang L, Shu Y (2024). AAV1-hOTOF gene therapy for autosomal recessive deafness 9: a single-arm trial. The Lancet, published online January 24, 2024 https://doi.org/10.1016/S0140-6736(23)02874-X.

Qi J, Tan F, Zhang L, Lu L, Zhang S, Zhai Y, Lu Y, Qian X, Dong W, Zhou Y, Zhang Z, Yang X, Jiang L, Yu C, Liu J, Chen T, Wu L, Tan C, Sun S, Chai R. AAV-medicated gene therapy restores hearing in patients with DFNB9 deafness. Advanced Science, 11(11), e2306788. DOI: 10.1002/advs.202306788.

Vignesh SS, Jaya V, Muraleedharan A. (2016). Prevalence and Audiological Characteristics of Auditory Neuropathy Spectrum Disorder in Pediatric Population: A Retrospective Study. Indian Journal of Otolaryngology Head and Neck Surgery, 68(2), 196–201. doi: 10.1007/s12070-014-0759-6.

Akouos’s Gene Therapy Trial for OTOF-mediated Hearing Loss (AK-OTOF-101)

• Global, multicenter, phase 1/2 trial in individuals with sensorineural hearing loss due to otoferlin gene (OTOF) mutations
  • AK-OTOF to be administered via a one-time unilateral intracochlear administration using a transcanal approach
• Key eligibility criteria include: 
  • Participant may be of any age, based on cohort criteria
  • Confirmed otoferlin gene mutations
  • Clinical presentation of Profound sensorineural hearing loss as assessed by auditory brainstem response
  • Preserved otoacoustic emissions
  • Does not have bilateral cochlear implants

For additional information about the trial, please see the following link: https://clinicaltrials.gov/study/NCT05821959

For information about no-charge genetic testing and counseling for sensorineural hearing loss, please see the following link: Akouos Resonate Test - PreventionGenetics