Abstract
Gene therapy has recently restored natural audibility in humans with OTOF-gene mutations. This biological restoration of hearing is different from cochlear implantation (CI) that produces artificial hearing via electric stimulation of the auditory nerve. In three published trials, 21 DFNB9 patients show 244 grade I/II adverse events (AEs), 2 grade III AEs and no serious AEs. The average gene therapy effect is substantial (52.4-dB improvement from baseline complete deafness), rapid (0.74-month time constant), and stable over the initial six months. However, individual outcomes vary from restored normal audibility (≤20 dB HL) to severe hearing loss (≥80 dB HL). Here critical knowledge gaps in gene therapy are identified such as understanding the individual variability, assessing temporal processing, and comparing efficacy with cochlear implantation. It is predicted that gene therapy will include patients with less than complete hearing loss and target other monogenic forms of congenital deafness. Advanced technologies in minimally invasive drug delivery and gene editing will further increase the safety, efficacy and applicability of gene therapy for hearing loss. Cochlear implantation likely remains the standard intervention for severe-to-profound hearing loss, but gene therapy will emerge as a viable alternative in treating monogenic forms of deafness.