Third-generation lentiviral gene therapy rescues function in a mouse model of Usher 1BThird-generation lentiviral gene therapy rescues function in a mouse model of Usher 1B

Introduction Usher syndrome 1B is characterized by congenital deafness, loss of vestibular function and blindness. The underlying genetic mutations affects the myosin-VIIa (MYO7A) gene. Homozygous Shaker-1 mice, which develop hearing and balance loss in their postnatal period due to Myo7a mutation are an excellent model to mimic human Usher 1B syndrome and can be used for the development of new gene therapeutic treatment strategies.

Methods A novel third-generation, high-capacity lentiviral vector system was used to deliver MYO7A cDNA plus a dTomato reporter gene in one vector. The efficacy of the vector was investigated in vitro in the cochlea-derived cell line HEI-OC1 and in vivo in heterozygous and homozygous Shaker-1 mice.

Results MYO7A and dTomato were successfully expressed in HEI-OC1 after transduction with the lentiviral vector system. Application of the MYO7A lentiviral vector to normal hearing mice did not affect hearing. A partial recovery of auditory function and improved balance was achieved after delivery of MYO7A at postnatal day 17 with the lentiviral vector to homozygous Shaker-1 mice. Heterozygous animals developed severe hearing loss across all frequencies at the age of 6 months. Interestingly, heterozygous Shaker-1 mice treated with lentiviral MYO7A gene therapy maintained hearing thresholds similar to wild-type littermates.

Conclusion This is to our knowledge, the first report on the efficacy of lentiviral vector technology in the inner ear to treat a hearing and balance disorder in heterozygous and homozygous Shaker-1 mice.

ERC Grant iHear to Axel Schambach; German Research Foundation Cluster of Excellence H4A

Publikationsverlauf

Artikel online veröffentlicht:
12. Mai 2023