LATE ONSET HEARING IMPAIRMENT: FROM DISEASE MECHANISMS TO THERAPY – HearInNoise

Hearing impairment, the most frequent sensory deficit, causes communication difficulties, often associated with social isolation, depression and reduced physical and cognitive function, with a dramatic economic impact on healthcare systems worldwide. Whatever the cause, genetics, environmental factors, or aging; the pathology of hearing deterioration often includes irreversible damage of sensory hair cells and/or the associated auditory primary neurons.
So far, tremendous progress has been made regarding the mechanisms of congenital and early hearing loss, but we know very few about the key hearing pathways critical in late-onset, progressive hearing impairments. Building upon our interdisciplinary studies of the congenital profound deafness, the HearInNoise initiative is designed, to focus on the late-onset and progressive hearing impairments. These sensory deficits offer the possibility to intervene before irreversible damage, provided appropriate therapeutic targets are identified and validated in the appropriate preclinical animal models.
The project stems from ongoing work in mutant mice lacking clarin-1, a tetraspan-like protein whose defect is responsible for post-lingual hearing loss in humans, combined with vision loss. In an ENU-phenotype driven screen, newly identified mutation was observed in clarin-2 causing late onset hearing impairments in mouse, supporting a key role of this clarin family in the inner ear. Ongoing work point to defects in structural organization of both the hair bundle and the synapses between the auditory inner hair cells and associated neurons. In a pilot experiment, viral-mediated gene supplementation prevents hearing impairment, indicating that the late-onset and progressive hearing impairment in the clinically relevant animal models allows a time window for therapeutic interventions more suitable to halt the disease.
HearInNoise brings together a wide spectrum of cutting-edge knowledge and technology in the fields of molecular biology, “Omics”, biochemical and computational analyses, cell biology, imaging, and physiology techniques to i) identify new actors in hearing processing, iii) better understand the related-disease mechanisms and relationship with environment, and iv) devise and validate solutions for the underlying pathogenic processes.
More specifically, from properties of the causal proteins (link to the cytoskeleton, and/or membranes; search of the their protein-protein interactomes) up to the full characterization of the corresponding animal models, we will identify and dissect the key pathways underlying the hearing deficits. We will investigate how the interplay between genes governing cochlear integrity and environmental factors (especially noise), and age would impact hearing deterioration. By using hair cell- and neuronal-specific suppression of causative genes, we will unlock the mechanisms underpinning the dialog between the auditory pre- and post-synaptic regions, and how such crosstalk impacts on the maintenance of normal neuronal projections. The deaf mutant mice will be investigated in standard and challenged conditions (noise exposure, at varying age time points) aiming to identify key processes that might constitute targets for therapeutic interventions. In this context, we will also implement innovative ear viral- and drug-delivery approaches, aiming to prevent and/or slow down the disease progression.
By providing fundamental insights into disease-associated pathways in both normal and pathogenic conditions, and their links with environmental factors, the HearInNoise project, performed in a framework of fruitful national and international collaborations, should generate new basic research discoveries and identify targets for preserving the remaining activity of the auditory sensory cells, and/or associated neurons, with potential applications to other forms of neurosensory disorders, including noise-induced and age-related hearing impairment.