Efficient and precise generation of Tay–Sachs disease model in rabbit by prime editing system
Yuqiang Qian, Ding Zhao, Tingting Sui, Mao Chen, Zhiquan Liu, Hongmei Liu, Tao Zhang, Siyu Chen, Liangxue Lai, Zhanjun Li
Abstract
Tay-Sachs disease (TSD) is a progressive neurodegenerative disorder due to an autosomal recessively inherited deficiency of -hexosaminidase A (HexA) 1 . The four-bases (TATC) insertion in exon 11 of the HEXA (HEXA ins TATC) accounts for 80% of Tay-Sachs disease from the Ashkenazi Jewish population 2 . However, no typical clinical phenotypes, such as neurological abnormalities, the restricted pattern of distribution of GM2-ganglioside and membranous cytoplasmic bodies in the brain, were observed in HEXA -/-mouse models, due to the difference in the ganglioside degradation pathways in mice and human 3 . Thus, it is desired to generate an ideal animal model to accurately mimic HEXA ins TATC in TSD patients. CRISPR-Cas9 systemmediated HDR 4 has been used to generate the mutation of HEXA ins TATC, however, low efficiency and high indels impede its application.