Aziz El-Amraoui

Bio After a PhD in Neuroscience from the University of Lyon-I in 1995, Dr Aziz El-Amraoui joined the Institut Pasteur (Paris) where through identification and characterization of dpzen novel deafness genes he has been able to provide major insights into fundamental and medical aspects of hearing & vision functioning and related disorders ( Multidisciplinary and multiscale approaches owing to the biochemical properties of deafness genes’ encoded proteins, identification of their molecular networks, deep-phenotyping of related disease animal models enabled clear understanding of how the inner ear & eye sensory organs develop and function (Jean-Valade Award 2005, Fond Mazet-Danet Fondation de France, 2006; Chaire of Excellence Charles Nicolle, Institut Pasteur (2017). Building on accurate and well-documented disease pathogenic mechanisms, his team current efforts are focused on late-onset and/or progressive hearing and vision impairments, from pathogenesis to treatment solutions. The major aims of the team are to i) understand how our sense organs ensure and maintain normal functioning throughout life, ii) identify sensory (hearing, with or without balance or vision loss) disease-causal genes & the underlying pathogenic pathways, iii) elucidate how genes-environment (e.g., light and noise exposure) interplay impacts sense deterioration, and iv) seek potential treatment solutions to delay, prevent and/or cure progressive hearing in animal preclinical models, and accelerate their transfer into clinics.

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Subtitle New opportunities for a long-sought quest: corrective gene replacement therapies in the inner ear

Summary Hearing impairment is the most common sensory disorder in humans. While prosthetic devices, such as cochlear implants, help alleviate the burden of hearing loss in a subpopulation of deaf patients, effective biological treatments of cochlear functions are still missing. Promising successes using adeno-associated virus (AAV)-mediated therapeutics have been obtained recently, often with only partial recovery of all or certain sound frequencies. Several challenges such as efficiency (for all frequencies), long term stability, and therapeutic window need to be addressed/tackled. To address these issues, we used distinct deaf animal models defective for two tetraspan-like proteins, members of the clarin (CLRN) family. Defects in CLRN1 or CLRN2 were recently found to cause hearing deficits in humans, mice, and zebrafish, supporting evolutionary conservation of the key role of the two clarin proteins in the inner ear. Constitutive or conditional inactivation of either, or both, clarin genes lead to sensory deficits that reflect different clinical conditions observed in humans, with hearing loss being congenital and profound or post-natal and progressive, and sometimes also associated with severe balance deficits. As gene therapies continue to evolve with promising success for the treatment of rare diseases, we used these distinct clarin-deficient models to monitor and document the beneficial outcomes of viral-mediated gene replacement therapeutics according to the type of sensory deficits. Our findings pinpoint the importance of the therapeutic window, and a significant correlation between the extent of sensory recovery and the type and age at onset of targeted deficit.