|Association for Research in Otolaryngology|
|39th Midwinter Meeting FEBRUARY 20-24, 2016|
|Poster Reference ID: 0693-000251|
|Title Effective Protection Against Severe Noise-Induced Hearing Loss by an Inner Ear Penetrating, Small Molecule Clinical Drug Candidate Following Daily, Post-Trauma Systemic Administration|
Sensorineural hearing loss is caused by damage to the sensory hair cells and neurons of the cochlea and is the most common type of permanent hearing loss (American Speech-Language-Hearing Association; ASHA). Among adults, the 2 main causes of sensorineural hearing loss are excessive noise exposure and aging (Hearing Loss Association of America; HLAA). Currently no approved pharmaceutical treatment exists and recent meta-analysis of the standard-of-care, off-label use of corticosteroid therapy have concluded that neither systemic nor intratympanic administration has any significant treatment effect (Crane et al. 2015, Laryngoscope 125(1):209-17). We here demonstrate that the small molecule, clinical drug candidate SENS-218 significantly reduces permanent hearing loss and loss of outer sensory hair cells in a rat model of severe noise induced hearing loss after daily, post-trauma, systemic administration.
Following baseline audiometry, 7 week old awake and behaving male Wistar rats were exposed to 120 dB octave band noise (8-16 kHz) for 2 hours on a slowly rotating platform in a sound-attenuating cubicle. SENS-218 (n=7) or placebo (n=7) treatment was initiated after the end of acoustic trauma exposure using intraperitoneal administration and continued daily until day 13.
Both SENS-218 and placebo treated animals displayed up to ~60 dB temporary ABR threshold shifts at 24h (8/16/24 kHz) accompanied by strong or complete suppression of DPOAE amplitudes (4/8/16/24/32 kHz). However, on day 14, SENS-218 treated animals displayed up to ~60% lower permanent ABR threshold shifts and up to ~60% higher DPOAE amplitudes. Taking into account potential variability of individual acoustic trauma, both recovery of ABR thresholds and DPOAE amplitudes from 24h to day 14 were also determined to be significantly improved after SENS-218 treatment. The functional audiometry data were supported by significantly reduced mean outer hair cell loss after drug treatment determined from cochleograms constructed from cell counts in fixed cochlea at day 14.
In an additional cohort of animals, significant nanomolar exposure-levels of SENS-218 were quantified in samples of both perilymph and inner ear tissue after single intraperitoneal administration for at least 4 hours, with a time-course following that of blood plasma samples from the tail-vein.
Altogether, these results demonstrate that daily, systemic administration of the small molecule clinical candidate drug SENS-218 with demonstrated inner ear penetration strongly and significantly protects against permanent hearing loss and cochlear cell loss when treatment is initiated after severe acoustic overexposure.