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

Abstract

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.

Allele-specific gene editing prevents deafness in a model of dominant progressive hearing loss

“…Our results represent a significant improvement over previous strategies, where hearing preservation was modest and not sustained even at low frequencies 16,22,23 . In the Gao et al study 16 , the limited durability may have been due to an insufficient number of transfected hair cells with lipid-mediated Cas9/gRNA delivery; the subsequent cell death may have resulted from non-cell autonomous factors, as described for genetic mutations that affect the retina 24 .…”

Generation of inner ear hair cells by direct lineage conversion of primary somatic cells

“…Recently the use of Anc80-based adeno associated vectors made inner ear gene delivery feasible ( Suzuki et al, 2017 ; Tao et al, 2018 ; Tan et al, 2019 ). The proof of concept studies have demonstrated functional recovery after administration of TMC1 gene therapy in animals carrying a mutation in the gene ( Yoshimura et al, 2019 ). Yet, the genetic causes of deafness are often unknown in patients, and loss of hair cells remains the leading contributor to hearing loss worldwide.…”

Inner Ear Gene Therapies Take Off: Current Promises and Future Challenges

“…Following this study, Yoshimura et al tested this artificial miRNA in the adult Beethoven mouse. They performed intracochlear injections of an AAV vector carrying the appropriate sequence at P15 and P30, and showed that miRNA-mediated gene silencing slowed the progression of hearing loss, improved inner hair cell survival, and prevented the degeneration of bundles of stereocilia in the adult mice [ 128 ]. However, no restoration of hearing or morphology was observed in mice treated at P84-P90, demonstrating that the effect of treatment depends on the age of the animal treated.…”