Extensive adaptive immune response of AAVs and Cas proteins in non-human primates

The CRISPR-mediated Cas system is the most widely used tool in gene editing and gene therapy for its convenience and efficiency. Delivery of the CRISPR system by adeno-associated viruses (AAVs) is currently the most promising approach to gene therapy. However, pre-existing adaptive immune responses...

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Bibliographic Details
Published inbioRxiv
Main Authors Chen, Yongchang, Xiao, Puhao, Bai, Raoxian, Zhang, Ting, Zhou, Yin, Zhou, Zhigang, Yan, Zhuo, Gong, Nannan, Liu, Jie, Ren, Shuaiwei, Wu, Ruo, Shen, Bin, Li, Shangang, Niu, Yuyu, Ji, Weizhi
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 25.03.2019
Subjects
Adaptive immunity
CRISPR
Gene therapy
Immune response
Nuclease
Primates
Transcription activator-like effector nucleases
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Summary:The CRISPR-mediated Cas system is the most widely used tool in gene editing and gene therapy for its convenience and efficiency. Delivery of the CRISPR system by adeno-associated viruses (AAVs) is currently the most promising approach to gene therapy. However, pre-existing adaptive immune responses against CRISPR nuclease (PAIR-C) and AAVs has been found in human serum, indicating that immune response is a problem that cannot be ignored, especially for in vivo gene correction. Non-human primates (NHPs) share many genetic and physiological traits with human, and are considered as the bridge for translational medicine. However, whether NHPs have same PAIR-C status with human is still unknown. Here, macaques (rhesus and cynomolgus), including normal housed and CRISPR-SpCas9 or TALENs edited individuals, were used to detect PAIR-C which covered SaCas9, SpCas9, AsCas12a and LbCas12a. Dogs and mice were also detected to expand the range of species. In addition, pre-existing adaptive antibodies to AAV8 and AAV9 were performed against macaques of different ages. The results showed that adaptive immunity was pre-existing in the macaques regardless of Cas proteins and AAVs. These findings indicate that the pre-existing adaptive immune of AAV-delivered CRISPR construction and correction system should be concerned for in vivo experiments.
DOI:10.1101/588913