Preclinical evaluation of the efficacy and safety of AAV1-hOTOF in mice and non-human primates

Abstract

AbstractPathogenic mutations in theOTOFgene cause autosomal recessive hearing loss 9 (DFNB9), one of the most common forms of auditory neuropathy. There is no biological treatment for DFNB9. Here, we designed anOTOFgene therapy agent by dual AAV1 carrying humanOTOFcoding sequences with the expression driven by the hair cell-specific promoterMyo15, AAV1-hOTOF. To develop a clinical application of AAV1-hOTOF gene therapy, we evaluated its efficacy and safety in animal models by pharmacodynamics, behavior, and histopathology. AAV1-hOTOF inner ear delivery significantly improved hearing inOtof−/−mice without affecting normal hearing in wild-type mice. AAV1 was predominately distributed to the cochlea although it was detected in other organs such as the central nervous system and the liver, and no obvious toxic effects of AAV1-hOTOF were observed in mice. To further evaluate the safety ofMyo15promoter-driven AAV1-transgene, AAV1-GFP was delivered into the inner ear ofMacaca fascicularisvia the round window membrane. AAV1-GFP transduced 60-94% of the inner hair cells along the cochlear turns. AAV1-GFP was detected in isolated organs and no significant adverse effects were detected. These results suggest that AAV1-hOTOF is well tolerated and effective in animals, providing critical support for its clinical translation.