"This work is motivated by the possibility of 'efferent gene therapy' as a therapeutic strategy. Is this feasible? Gene therapy for inner ear disease has advanced significantly, largely to correct 'deafness genes' that underlie inherited hearing loss. Notably, clinical trials for replacement, or editing of mutant otoferlin (DFNB9) are underway in several countries [48, 49]. Additional strategies to prevent or ameliorate ototoxic damage (as from antibiotics or chemotherapeutics) seek small molecules to address mitochondrial function, generation of reactive oxygen species, or aspects of calcium excitotoxicity. Prevention or reduction of noise-induced hearing loss however, remains largely the domain of protective coverings, or avoidance of acoustic trauma...
Any future therapeutic must cross the blood/labyrinth barrier and avoid deleterious side effects. This may be a smaller problem due to the unique pharmacology and restricted expression of α9α10 nAChRs that have not been shown to function elsewhere in the nervous system[53]. However, a significant body of evidence has shown α9 expression in lymphocytes and implicated their activity in inflammatory pain [54-56]. Such concerns will be greater if regular dosing is required for protection from daily exposure to noise. A gene therapy strategy offers some advantages. Direct application to the inner ear fluid space would greatly minimize, if not eliminate, side effects. If viral expression is sufficiently long-lasting there may be no need for repeated dosing. The drawbacks are that viral injection is time-consuming, requires surgical expertise, and is intimidating compared to an oral or injectable medication. Nonetheless, the risk/benefit profile might be compared favorably to that for cochlear implants where the surgical risks are higher, but the benefit well-established. Should efferent gene therapy be effective, the benefit for those at risk of early onset presbycusis and unavoidable noise exposure may justify the additional challenges. A second potential application is for those suffering painful hyperacusis, or noxacusis. If as proposed, type II cochlear afferents signal acoustic pain[57-60], enhanced efferent inhibition of glutamate release from OHCs onto type II afferents may be particularly beneficial for this condition."