A dual-AAV approach rescues auditory function in deaf otoferlin knock-out mice
On December 3rd, the result was published in the journal EMBO Molecular Medicine by " A dual-AAV approach restores fast exocytosis and partially rescues auditory function in deaf otoferlin knock-out mice". The study reveals a promising and effective means to ameliorate hearing loss, and proposes a gene therapy mediated by dual-AAV vectors to treat deafness caused by mutations in large genes such as Otof. Considering the limited AAV cargo capacity of approximately 4.7–5 kb, it is difficult to transfer the 6 kb-long otoferlin cDNA into transgenic animals. Specifically, in this study, taking advantage of the dual‐AAV trans‐splicing and the hybrid strategy, the scientists first carefully generated the dual-AAV2/6 vectors. Both strategies can bring about re‐assembly of the two otoferlin cDNA fragments and expression of full‐length otoferlin. In a word, this paper proposes a gene therapy mediated by dual‐AAV vectors to treat deafness caused by OTOF gene mutations, suggesting that dual-AAV vector systems are suitable for the delivery of large transgenes into transgenic mice, which may pave the way for future gene replacement therapies of recessively inherited deafness forms like DFNB9.
1. Otoferlin, defective in a human deafness form, is essential for exocytosis at the auditory ribbon synapse
2. A dual-AAV approach restores fast exocytosis and partially rescues auditory function in deaf otoferlin knock-out mice