AAV Gene Therapy Rescues Hearing in a Mouse Model of SYNE4 Deafness
2School of Neurobiology, Biochemistry and Biophysics, Faculty of Life Sciences, Tel Aviv University, Israel
3Departments of Otolaryngology & Neurology, Boston Children’s Hospital & Harvard Medical School, USA
SYNE4 codes for nesprin 4, a member of the linker of nucleoskeleton and cytoskeleton (LINC) complex, that mediates nucleus positioning in cochlear hair cells. Pathogenic variants in SYNE4 have been found to lead to progressive deafness in humans (DFNB76) and mice. In order to develop gene therapy for this form of deafness, we used AAV9-PHP.B, a recently developed synthetic adeno-associated virus, to express the coding sequence of Syne4 in the hair cells of neonatal Syne4-/- mice. We delivered the virus into the inner ear by local injection into the posterior-semicircular canal and observed transduction of all inner and outer hair cells. This resulted in long-term rescue hair cell morphology and survival, and preservation of hearing, demonstrated by auditory-brainstem response (ABR), distortion-product otoacoustic emissions (DPOAE), and auditory-associated behaviors. No adverse effects on hearing were observed following treatment. While the exact time window for intervention in humans is not clear, the gradual progressive hearing loss observed in humans seems encouraging for this or a similar approach of gene therapy to prevent hearing loss in humans with SYNE4 deafness. More broadly, our results validate AAV9.PHP.B as an excellent vector for gene therapy on target genes that are expressed in hair cells.