Targeted Allele Suppression Prevents Progressive Hearing Loss in the Mature Murine Model of Human TMC1 Deafness

• Published in: Molecular therapy Vol. 27; no. 3; pp. 681 - 690
• Main Authors: Yoshimura, Hidekane, Shibata, Seiji B., Ranum, Paul T., Moteki, Hideaki, Smith, Richard J.H.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 06.03.2019; Elsevier Limited; American Society of Gene & Cell Therapy
• Subjects: adeno-associated virus; Age; Animal models; Animals; Cell survival; Cochlea; Cochlea - metabolism; Cochlea - physiopathology; Cochlea - ultrastructure; Cytomegalovirus; Deafness; Deafness - genetics; Deafness - physiopathology; Degeneration; Dependovirus - genetics; Disease Models, Animal; Ear; Ear, Inner - metabolism; Ear, Inner - physiopathology; Ear, Inner - ultrastructure; Ears & hearing; Gene silencing; Gene therapy; Genetic Therapy; Genetic Vectors - genetics; Gestational age; Hearing loss; Hearing Loss - genetics; Hearing Loss - physiopathology; Humans; Immunohistochemistry; inner ear; Maturation; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mice, Inbred C3H; MicroRNAs; Microscopy, Electron, Scanning; miRNA; Neonates; Organ of Corti; Original; Quality of life; RNA Interference; RNA-mediated interference; Scanning electron microscopy; Studies; vestibule; Vestibule, Labyrinth - metabolism; Vestibule, Labyrinth - physiopathology; Vestibule, Labyrinth - ultrastructure; United States > US; cochlea; gene therapy; adeno-associated virus; vestibule; hearing loss; inner ear
• ISSN: 1525-0016; 1525-0024; 1525-0024
• DOI: 10.1016/j.ymthe.2018.12.014

Hearing loss is the most common human sensory deficit. Its correction has been the goal of several gene-therapy based studies exploring a variety of interventions. Although these studies report varying degrees of success, all treatments have targeted developing inner ears in neonatal mice, a time point in the structural maturation of the cochlea prior to 26 weeks gestational age in humans. It is unclear whether cochlear gene therapy can salvage hearing in the mature organ of Corti. Herein, we report the first study to test gene therapy in an adult murine model of human deafness. Using a single intracochlear injection of an artificial microRNA carried in an AAV vector, we show that RNAi-mediated gene silencing can slow progression of hearing loss, improve inner hair cell survival, and prevent stereocilia bundle degeneration in the mature Beethoven mouse, a model of human TMC1 deafness. The ability to study gene therapy in mature murine ears constitutes a significant step toward its translation to human subjects. Smith and colleagues demonstrate the effect of cochlear gene therapy in an adult murine model of human TMC1 deafness and show that RNAi-mediated gene silencing slows progression of hearing loss, suggesting a significant step toward its application in human subjects.