AAV Gene Therapy Rescues Hearing in a Mouse Model of SYNE4 Deafness

Pathogenic variants in SYNE4 are known to lead to deafness in humans from Israel (Horn H, Brownstein Z et al, J Clin Invest, 2013) and Turkey (Masterson J et al, Balkan Med J, 2018). The Syne4 gene encodes a protein that is part of the linker of nucleoskeleton and cytoskeleton (LINC) complex in the nuclear envelope, named Nesprin 4 (Nesp4). LINC complexes couple nuclear components to the cytoskeleton and mediate nuclear polarization. Our data demonstrate that loss of Syne4 in mice leads to a rapid loss of OHC that begins at the onset of electromotility, suggesting a role for Syne4 in OHC maturation. In order to design a genetic therapy that would overcome the limited therapeutic window, we cloned the coding sequence of Syne4 into an AAV backbone and encapsulated it in a recently developed synthetic AAV named Anc80L65. We show that injection of AAV containing the coding sequence of Syne4 leads to enhanced OHC survival and recovery of auditory brainstem response (ABR). Anc80L65 was recently shown to transduce HC in non-human primates as well, demonstrating its potential relevance for gene therapy in humans. As the Syne4 knock-out mouse phenotype mimics the human one, these mice are a relevant model for development of gene therapy for human hearing loss.