Based on DNA: An in vivo Gene Editing Strategy to Treat Congenital Deafness
On July 12, 2022, Wei XIONG lab in Chinese Institute for Brain Research, Beijing (CIBR) published a research article in the journal Cell Reports titled: Template-independent genome editing in the Pcdh15av-3j mouse, a model of human DFNB23 nonsyndromic deafness. This work demonstrates that non-homologous end joining (NHEJ) can be leveraged to efficiently and effectively restore frameshift mutation induced genetic diseases in mammals.
Abstract
Although frameshift mutations lead to 22% of inherited Mendelian disorders in humans, there is no efficient in vivo gene therapy strategy available to date, particularly in non-dividing cells. Here, we show that non-homologous end joining (NHEJ) mediated non-random editing profiles compensate the frameshift mutation in the Pcdh15 gene and restore the lost mechanotransduction function in postmitotic hair cells of Pcdh15av-3j mice, an animal model of human nonsyndromic deafness DFNB23. Identified by an ex vivo evaluation system in cultured cochlear explants, the selected guide RNA restores reading frame in approximately 50% of indel products and recovers mechanotransduction in more than 70% targeted hair cells. In vivo treatment shows that half of the animals gain improvements in auditory responses and balance function is restored in the majority of injected mutant mice. These results demonstrate that NHEJ-mediated reading-frame restoration is a simple and efficient strategy in postmitotic systems.
Achievements
With the technological breakthrough of gene delivery and gene expression in humans, gene therapy for hereditary diseases is becoming more and more prospective for translational study. The advent of CRISPR-Cas technology in 2011 provided a practical toolbox, making in vivo gene editing possible. Gene replacement/silencing can usually only cure the symptoms at the mRNA level, while the gene-editing based strategy can allow one time treatment but permanent effects. This frame-restoration strategy shows a great potential for correcting inherited frame-shifting mutations.
About the authors
The co-first authors of the paper are three doctoral students: Lian LIU, Linzhi ZOU, and Kuan LI. This work is a collaboration with Fangyi CHEN laboratory at Southern University of Science and Technology, Xu Zhigang XU laboratory at Shandong University, and Qianwen SUN laboratory at Tsinghua University. The corresponding author is Dr. Wei XIONG.
About XIONG lab
XIONG laboratory was established in 2015. Besides gene therapy for hereditary deafness, two other main directions, molecular and cellular mechanisms of hair-cell mechanotransduction and neural mechanisms of sound processing, were focused in the lab. All lab members are extremely enthusiastic to develop all technologies and resources to address these questions.
Article address: https://doi.org/10.1016/j.celrep.2022.111061
