Efficient and precise generation of Tay–Sachs disease model in rabbit by prime editing system

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.