Publication shows AM-111's otoprotective effect in cochlear ischaemia
The December 2011 issue of the scientific journal Otology & Neurotology has featured new data on the otoprotective effects of AM-111, Auris Medical's intracellular JNK ligand. In an article entitled, "Protection Against Ischaemic Cochlear Damage by Intratympanic Administration of AM-111", a research group led by Professor Kiyofumi Gyo from the Department of Otolaryngology of Ehime University, Japan, showed the results of a study with AM-111 in an animal model of transient cochlear ischaemia. Vascular disturbances such as an acute interruption of the blood supply to the cochlea are one of the factors that can trigger sudden sensorineural hearing loss.
The Japanese scientists used a previously established model of transient cochlear ischaemia for the study. In this model, the vertebral artery of gerbils is occluded for 15 minutes in order to provoke transient cochlear ischaemia, followed by reperfusion. This leads to irreversible loss, particularly of inner hair cells and permanent hearing loss, particularly at higher frequencies. 10Âµl of AM-111 at a concentration of 1, 10 or 100ÂµM and formulated in a gel was placed onto the round window membrane 30 minutes after the insult. The gel without active substance served as control. For the evaluation of the auditory function, auditory brainstem responses (ABRs) were measured at 2, 4 and 8kHz before ischaemia, as well as four and seven days after the temporary arterial occlusion. Animals were sacrificed on day seven for histopathology and counting of hair cells.
In control ears, mean ABR thresholds increased substantially to day four (+31 dB at 8kHz, the most sensitive frequency) and from there recovered slightly to day seven (+25 dB at 8kHz). In contrast, ears treated with AM-111 showed less hearing loss the higher the applied concentration was. At the highest concentration, mean ABR thresholds in AM-111 protected ears rose by only 7 dB to day four and were elevated by 3 dB on day seven. Statistical analysis (one-way analysis of variance followed by Fisher's post hoc test) revealed statistical significance of the otoprotective effect of AM-111 at all three concentrations (p<0.01 at 100 and 10ÂµM, and p<0.05 at 1ÂµM). The protective effect was confirmed by histopathology: inner hair cell loss on day seven in the most affected basal turn amounted to 13.3 Â± 2.7 per cent in controls and 3.1 Â± 0.6 per cent in the highest concentration AM-111 group. The difference was statistically significant in a concentration dependent fashion (p<0.01 at 100 and 10ÂµM, and p<0.05 at 1ÂµM).
AM-111 is a cell-permeable peptide that selectively blocks JNK MAPK mediated apoptosis of stress injured hair cells and neurons in the cochlea. Major cochlear stress incidents that may result in irreversible hearing loss include exposure to excessive noise, disturbances of the blood supply, viral or bacterial infections, and exposure to certain ototoxic substances. When administered within a therapeutic window after the incident, AM-111 can effectively protect cochlear hair cells and neurons that would otherwise undergo apoptosis and be lost forever. AM-111's otoprotective properties have been extensively tested and confirmed in various animal models so far, including acute acoustic trauma, acute labyrinthitis, surgery trauma, aminoglycoside ototoxicity, semicircular canal injury in otitis media and cochlear ischaemia. AM-111 has been granted orphan drug status in both the EU and US for the treatment of acute sensorineural hearing loss. The active substance of AM-111 has been in-licensed by Auris from Xigen.