“Erasure before choice is presented—to an individual, not their parents—is problematic [1].” According to Jaipreet Virdi, a deaf University of Delaware historian of medicine, technology, and disability, new gene therapy treatment approaches to deafness pose an ethical challenge between treating a disease that may limit access to our world, and how we view and value those with disabilities [1].
Akouos and Decibel Therapeutics are in the preclinical trial stages of testing gene therapies to treat autosomal recessive mutations such as OTOF [1]. OTOF creates severe hearing loss when both parents are carriers for the recessive gene that creates abnormal auditory brainstem response—indicating a defective pathway from the auditory nerve to the midbrain (the part of the brain that relays visual and auditory information) [2]. People with mutations in the OTOF gene are deficient in otoferlin—a protein needed for sensory cells to release neurotransmitters to activate auditory neurons [2].
The rationale behind the use of gene therapy to address this mutation is because the inner-ear is intact, and normal hair cell function is retained [1]. These therapeutic companies aim to deliver working copies of OTOF in order to produce otoferlin to restore hearing. This can lead to other genetic approaches to hearing loss for the future—with 50-60 percent of hearing loss attributed to genetics, and 8 percent of these mutations due to the OTOF gene [1].
Management of genetically-inherited deafness typically involves the use of hearing aids and cochlear implants. However, cochlear implants can damage cells in the inner ear—which people with OTOF mutations retain [1]. Cochlear implants allow people to process sound and stimulate the auditory nerve, however, they don’t allow for more complex sound-related differentiation from speech and background noise [1].
Akouos and Decibel Therapeutics use adeno-associated virus (AAV) approaches to deliver these gene therapies [3]. AAV is recognized by the cell surface receptors in host cells, which allows for the virus to be endocytosed—or taken in—by the cell. Once in the nucleus, it can hijack transcription to produce the desired protein, or integrate itself into the host genome [4].
In order to deliver this therapy to patients, a small incision is made behind the ear and injected into the cochlea. In experiments with mice that lacked the otoferlin protein, they were able to identify the recovery of hearing through the use of electrodes that identified their response to sound [4]. This same approach will be done for participants in the new trials that have expanded to the UK and Spain. These studies will last 2 years (Akouos) and 5 years (Decibel) respectively and each company is enrolling around 20 participants under the age of 18 [1].
This poses an incredible new opportunity to use a minimally invasive approach to treating genetically related hearing loss at an early age. Although it is recommended that these therapies be used for younger patients, correcting these genetic mutations can be done regardless of age. Additionally, hearing loss can impact a child both psychologically and cognitively. It can also lead to other social consequences and ostracization from institutions that are not as well versed at accommodating disabilities. Lastly, this can open new avenues to research for deafness that results from impacted hair follicles within the ear, or other genetic mutations.
However, any new approach to curing deafness comes with ethical dilemmas as it relates to the continued devaluation of those with disabilities. This argument is rooted in the assumption that a disability or abnormality is something that people living with deafness want to fix. This links back to what Virdi said—making this decision for young children that do not yet know their identity, values, or the social role of their condition is unethical. This delves into the challenge of informed consent—how are young children capable of providing informed consent without knowing the full extent of the meaning of deafness? This approach makes the choice for children who may not want to ‘fix’ their disability or find community as a result of their deafness.
This treatment can continue to further the erasure of deaf communities. Some may argue that instead of looking for a cure or treatment for deafness, we should instead work to provide better support for those with disabilities within institutions of work and education. Although this has been attempted by the establishment of the ADA, further advances could be made by advocating for broader social change and incorporating disability pride, awareness, and sign language into education systems.
Lastly, gene therapies may be challenged and be seen as an overmedicalization of disabilities like deafness. The desire to research and find a treatment for deafness not only defines it as something that is abnormal—continuing to ostracize deaf communities—but also leads to unnecessary medical intervention that may not necessarily improve their quality of life. Instead, this is something that quells our own definitions of illness, rather than addressing the social, political, and economic dilemmas that individuals with disabilities face.
Gene therapies provide an exciting new frontier for the treatment of genetically-linked deafness, and can provide a noninvasive solution for young children—allowing them to avoid the potential physical and social stressors of a lack of hearing. However, gene therapies that target young patients can be problematic in providing them overmedicalized treatment without them understanding the impact of their condition, in addition to the potential erasure and devaluation of deaf communities.
1. Mullin, E. (2023, October 20). New trials aim to restore hearing in deaf Children—With gene therapy. WIRED. https://www.wired.com/story/new-trials-aim-to-restore-hearing-in-deaf-children-with-gene-therapy/.
2. Azaiez H, Thorpe RK, Smith RJH. OTOF-Related Deafness. 2008 Feb 29 [Updated 2021 Jan 21]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1251/.
3. Ako_Admin. (n.d.). Our focus. Akouos. https://akouos.com/our-focus/#:~:text=AK%2DOTOF%20is%20intended%20to,affected%20cells%20of%20the%20cochlea.
4. Wang, D., Tai, P.W.L. & Gao, G. Adeno-associated virus vector as a platform for gene therapy delivery. Nat Rev Drug Discov 18, 358–378 (2019). https://doi.org/10.1038/s41573-019-0012-9.