Fuchs & Wood: Virally-Mediated Enhancement of Efferent Inhibition Reduces Acoustic Trauma in Wild Type Murine Cochleas

[StoneInFocus]

Noise-induced hearing loss (NIHL) poses an emerging global health problem with only ear protection or sound avoidance as preventive strategies. In addition, however, the cochlea receives some protection from medial olivocochlear (MOC) efferent neurons, providing a potential target for therapeutic enhancement. Cholinergic efferents release ACh (Acetylycholine) to hyperpolarize and shunt the outer hair cells (OHCs), reducing sound-evoked activation. The (α9)2​(α10)3​ nicotinic ACh receptor (nAChR) on the OHCs mediates this effect. Transgenic knock-in mice with a gain-of-function nAChR (α9L9'T) suffer less NIHL. α9 knockout mice are more vulnerable to NIHL but can be rescued by viral transduction of the α9L9'T subunit. In this study, an HA-tagged gain-of-function α9 isoform was expressed in wildtype mice in an attempt to reduce NIHL. Synaptic integration of the virally-expressed nAChR subunit was confirmed by HA-immunopuncta in the postsynaptic membrane of OHCs. After noise exposure, α9L9'T-HA injected mice had less hearing loss (auditory brainstem response (ABR) thresholds and threshold shifts) than did control mice. ABRs of α9L9'T-HA injected mice also had larger wave1 amplitudes and better recovery of wave one amplitudes post noise exposure. Thus, virally-expressed α9L9'T combines effectively with native α9 and α10 subunits to mitigate NIHL in wildtype cochleas.

Interesting part:

"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."