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- Title
The research of development of a miniature DNA base editor for DFNB9 gene therapy in hereditary deafness.
- Authors
Zhang, Z.; Wang, M.; Zhang, L.; Li, N.; Sun, Q.; Lu, Y.; Zhou, Y.; Tan, F.; Qi, J.; Chai, R.
- Abstract
OTOFERLIN (OTOF) mutation can lead to autosomal recessive deafness 9 (DFNB9), which is the main cause of auditory neuropathy. Delivering the exogenous OTOF gene through double AAV can restore the hearing of genetically deaf DFNB9 mice, but the efficacy of the gene replacement therapy may diminish over time, and it cannot really solve the deafness caused by the gene mutation. In contrast, gene editing can correct mutant genes at the DNA level and fundamentally treat hereditary deafness. We screened and developed a mini-base editor and optimised AAV expression elements for constructing a single AAV delivery base editing system to cure gene therapy of genetic deafness caused by OTOF point mutations. Specifically, we constructed mini-ABE and sgRNA (SchABE8e-sgRNA4) on a single AAV vector and screened out small promoter and short-polyA elements for the expression of the base editing system. At the same time, we found that targeting the promoter for expression in the reverse direction achieving a more efficient cleavage efficiency. We successfully restored the hearing of OTOF point mutant mice to WT level and maintained it for a long time by delivering the single-base editing system to the inner ear using AAV serotype-Anc80, which is capable of efficiently transducing inner ear hair cells. Subsequently, we evaluated the safety of the SchABE8e-sgRNA4 single-base editing system in WT mice and found that both vestibular and hearing levels were maintained at the WT level, indicating the safety of our delivery system. Taken together, these findings provide new strategies for treating DFNB9 in the clinic and lay the theoretical and experimental foundation for the clinical translation of gene editing therapy for deafness.
- Publication
Journal of Hearing Science, 2024, Vol 14, Issue 3, p142
- ISSN
2083-389X
- Publication type
Article