Viral gene therapy targeting inner ear supporting cells: from organoids to preclinical model for human deafness treatment – OrgaTherapEar

Deafness and balance defects are the most prevalent inherited sensory disorders in humans, and a major concern with serious costs for Public Health. About 80% of congenital deafness cases are of genetic origin. Several proofs of concept of inner ear gene therapy have been established in mouse model of human deafness paving the way for numerous promising clinical trials. One of these trials, known as AUDIOGENE, focuses on the DFNB9 deafness form caused by inner hair cell defects. Conducted by the Institut de l’Audition, the Sensorion company and Necker Hospital, this ongoing trial marked the first European endeavor in this specific area of research. These trials emphasize the successful translation of findings from mouse models to humans, particularly in identifying adeno-associated viral (AAV) vector as the preferred therapeutic vector. Gene therapy has now become a viable option for addressing many types of genetic deafness. However, a major limitation is the lack of specificity and low transduction rate of the AAV vectors in targeted cells. Therefore, it is crucial to uncover new AAV variants that can specifically and effectively transduce cells within the inner ear. The goal of OrgaTherapEar is to accelerate the identification of efficient AAV vectors to specifically target desired subset of cells within the sensory organ. We will combine the scalable 3D inner ear organoid technology with preclinical mouse model in order to identify improved therapeutic AAV vectors tailored to the inner ear cells whose function is altered in several forms of hereditary deafness. This will enhance the safety and effectiveness of therapeutic gene delivery into the inner ear with the perspective of fostering translational and clinical auditory research, while reducing the use of laboratory animals in translational research (Directive 2010/63/EU).