Researchgate profile: https://www.researchgate.net/profile/Aziz_El-Amraoui
Website : https://research.pasteur.fr/en/team/progressive-sensory-disorders-pathophysiology-and-therapy/
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.