Scalable human-compatible gene supplementation and genome editing therapies for genetic sensory disorders

Hearing, balance, and vision are essential for communication, mobility, and social integration, yet curative treatments remain unavailable for most inherited sensory disorders. Among these, Usher syndrome represents the leading cause of combined congenital deafness and progressive blindness, providing a unique and clinically relevant framework to develop gene-based therapeutic strategies across both the inner ear and the retina.

Recent advances in adeno-associated viral (AAV) vectors and next-generation genome editing technologies have opened realistic prospects for curative interventions. However, major challenges still limit clinical translation, including efficient delivery into post-mitotic sensory cells, durability of therapeutic benefit, definition of therapeutic windows, and safety, particularly with respect to immune responses and off-target effects.

This project aims to address these challenges by developing and validating scalable, human-compatible gene therapy strategies using clinically relevant models of Usher syndrome. It will leverage a unique set of humanized mouse models reproducing patient mutations, including newly developed conditional models with delayed sensory phenotypes, enabling investigation of therapeutic intervention before irreversible degeneration.

Two complementary therapeutic approaches will be explored. First, AAV gene supplementation will be used to restore expression of disease-causing genes that exceed standard vector capacity. This strategy has already demonstrated promising preliminary results, including preservation of vestibular function and delayed hearing loss in humanized models. Second, precision genome editing approaches, including base editing, will be developed to directly correct pathogenic mutations within their endogenous genomic context. This strategy offers a major advantage in terms of scalability, as it can be applied to a broad range of genes independently of coding sequence size.

Therapeutic outcomes will be assessed through an integrated, multiscale phenotyping pipeline combining molecular, structural, functional, and behavioral analyses in both the inner ear and the retina. The inner ear will serve as a rapid and quantitative testbed to evaluate therapeutic efficacy, while retinal studies will provide validation in a clinically relevant context, particularly for progressive vision loss.

Overall, the project will generate robust preclinical datasets defining efficacy, durability, safety, and therapeutic windows for gene supplementation and genome editing strategies. Beyond Usher syndrome, it will establish a transferable framework for the development of gene therapies targeting a wide range of inherited sensory disorders, with strong potential for clinical translation.

Le projet sera mené à l’Institut Pasteur, au sein de l’Institut de l’Audition, dans un environnement de recherche biomédicale d’excellence.

https://www.institut-audition.fr/

L’équipe développe des approches innovantes en thérapie génique et édition du génome pour les pathologies sensorielles, en s’appuyant sur des modèles murins humanisés et des plateformes technologiques de pointe.

https://research.pasteur.fr/en/team/progressive-sensory-disorders-pathophysiology-and-therapy/

Le doctorant évoluera dans un environnement interdisciplinaire, compétitif et fortement orienté vers la recherche translationnelle et les applications cliniques.

Nous recherchons un(e) candidat(e) d’excellent niveau académique, fortement engagé(e) dans un projet de carrière en recherche biomédicale.

Master 2 (ou équivalent) en biologie cellulaire/moléculaire, neurosciences, biotechnologies ou discipline apparentée

Résultats académiques excellents (top de promotion ou équivalent, classement apprécié)

Solide formation en biologie moléculaire et/ou cellulaire

Expérience expérimentale significative (stage long en laboratoire de recherche, idéalement avec modèles in vivo et/ou thérapie génique)

Capacité démontrée à mener un projet scientifique (autonomie, rigueur, esprit critique)

Forte motivation pour la recherche translationnelle et les approches innovantes (thérapie génique, édition du génome)

Aptitude à évoluer dans un environnement interdisciplinaire et collaboratif

Très bon niveau d’anglais scientifique (lecture, rédaction, communication)