Scientists from the Institut Pasteur, Inserm, Sorbonne University and the Collège de France, working in close collaboration with scientists from the University of Bordeaux, have recently elucidated the mechanisms of hearing loss associated with mutations in clarin-1, a molecule that plays an essential role in the auditory system. The absence of clarin-1 leads to a progressive hearing impairment, which could be prevented by gene therapy that targets the sensory hair cells in the inner ear. This discovery offers new prospects for the therapeutic treatment of individuals with hearing loss due to hair cell synaptopathies.
Hearing loss is the most common sensory deficit in humans. In France, about 6 million people have difficulties conversing because of a congenital or acquired hearing impairment. Hearing impairment is more common in older people, affecting a third of the population over the age of 60. To date, cochlear implants are the only available treatment for patients with hearing loss. These devices bypass damaged auditory sensory cells or hair cells and directly stimulate the auditory neurons, which transmit acoustic signals, converted into electrical signals, to the auditory cortex. The success of a cochlear implant is therefore largely dependent on the preservation of auditory neurons, as this ensures optimal transmission of the electrical impulses generated by the implant to the auditory cortex.
A deficiency in clarin-1 protein is known to cause Usher syndrome type III
Guided by the considerable progress made in our understanding of the mechanisms behind various forms of hearing loss, scientists are working on the development of alternative or complementary therapies to prevent and/or treat hearing impairments. One form of hearing loss being investigated by the teams led by Dr. Aziz El-Amraoui (Institut Pasteur), Dr. Didier Dulon (Bordeaux Neurocampus) and Prof. Christine Petit (Institut Pasteur and Collège de France), associated with Inserm, and Sorbonne University Association, is Usher syndrome type III (USH3). Patients with this syndrome present:
- progressive postlingual hearing loss (hearing loss after language acquisition);
- variable vestibular dysfunction;
- retinitis pigmentosa, which may appear at any age.
Only one USH3 gene has currently been identified; it encodes a protein known as "clarin-1". "In a model of this mutation, the absence of clarin-1 leads to failure of synaptic transmission between the hair cells in the inner ear and the auditory neurons," explains Dr. Aziz El-Amraoui. The scientists therefore decided to investigate the mechanisms behind this late-onset deafness and explore potential treatment possibilities.
Discovery of a new role of clarin-1
Scientists from the Institut Pasteur, working closely with Dr. Didier Dulon (Inserm, University of Bordeaux) and with the contribution of Prof. Paul Avan (University of Auvergne), reproduced and characterized the mechanisms underlying the hearing loss caused by this syndrome in animal models. Molecular, morphological and audiometric explorations, together with electrophysiological analyses of the activity of auditory hair cells, revealed a new role of clarin-1, in addition to its involvement in the functioning of the hair bundle, the structure that converts sound into electrical signals. By ensuring a tight coupling between the synaptic ribbons and the voltage-dependent calcium channels located on the synaptic membrane of inner hair cells, clarin-1 plays an essential role in organizing the morphology and functional efficacy of this synapse, which is responsible for transferring information between the sensory cell and the neurons that form the auditory nerve.
New hope for treating individuals with hearing loss
The scientists demonstrated that a single cochlear injection of a nucleotide sequence encoding clarin-1 (via a safe AAV-type viral vector) results in long-term preservation of hearing by maintaining the normal subcellular and molecular organization of the synapses in auditory hair cells. As Dr. A. El-Amraoui, co-senior author of the paper with Dr. D. Dulon and Prof. C. Petit (Director of the Genetics & Physiology of Hearing Unit at the Institut Pasteur), explains: "Our results confirm that gene therapy approaches could be used as an effective treatment method for conditions affecting the auditory synapses and may also be applied more generally to other types of hearing loss in conjunction with a cochlear implant, to preserve auditory neurons and improve the transmission of signals to the brain."The scientists' research, which was published on July 9 in the Journal of Clinical Investigation, therefore raises new prospects for the therapeutic treatment of individuals with hearing loss.
The teams will now explore combinatorial therapy approaches (for example combining gene therapy with cochlear implantation), with the aim of optimizing the preservation of auditory neurons and their synapses. This would offer benefits not only for many forms of hereditary hearing loss but also for noise-induced and age-related hearing loss.
This research received funding from the French National Research Agency (ANR), the Investing in the Future program (Ligh4deaf, ANR-15-RHUS-0001), ANRHearInNoise (ANR-17-CE16-0017), LHW-Stiftung, the BNP Paribas Foundation and the Agir pour l'Audition Foundation.
Clarin-1 gene transfer rescues auditory synaptopathy in model of Usher syndrome, J. Clin. Invest., July 9, 2018.
Didier Dulon,1,2,*, Samantha Papal,1,3,4, Pranav Patni,1,3,4, Matteo Cortese,1,3,4, Philippe F.Y. Vincent,1,2, Margot Tertrais,1,2, Alice Emptoz,1,3,4, Aziz Tlili,1,3,4, Yohan Bouleau,1,2, Vincent Michel,1,3,4, Sedigheh Delmaghani,1,3,4, Alain Aghaie,1,3,4, Elise Pepermans,1,3,4, Olinda Allegria-Prevot,1,3,4, Omar Akil,5, Lawrence Lustig,6, Paul Avan,7, Saaid Safieddine,1,3,4,8, Christine Petit,1,3,4,9,* and Aziz El-Amraoui1,3,4,*.
1. UMRS 1120, Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France.
2. Université de Bordeaux, Laboratoire de Neurophysiologie de la Synapse Auditive, Bordeaux Neurocampus, Bordeaux, France.
3. Unité de Génétique et Physiologie de l’Audition, Institut Pasteur, Paris, France.
4. Sorbonne Universités, Complexité du Vivant, Paris, France.
5. Department of Otolaryngology–Head and Neck Surgery, UCSF, San Francisco, California, USA.
6. Department of Otolaryngology–Head and Neck Surgery, Columbia University Medical Center, New York, USA.
7. Laboratoire de Biophysique Sensorielle, Faculté de Médecine, Université d’Auvergne; Biophysique Médicale, Centre Jean Perrin, Clermont-Ferrand, France.
8. Centre National de la Recherche Scientifique, Paris, France.
9. Collège de France, Paris, France.
* Co-senior & corresponding authors