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Editor’s note iNature is China’s largest academic official account.
It is jointly created by the doctoral team of Tsinghua University, Harvard University, Chinese Academy of Sciences and other units.
The iNature Talent Official Account is now launched, focusing on talent recruitment, academic progress, scientific research information, interested parties can Long press or scan the QR code below to follow us
.
iNatureTay-Sachs disease (TSD) is a progressive neurodegenerative disease due to an autosomal recessive genetic defect in β-hexosaminidase A (HexA)1
.
The four base (TATC) insertion in exon 11 of HEXA (HEXA ins TATC) accounts for 80% of Tay-Sachs disease in Ashkenazi Jewish population
.
However, due to differences in mouse ganglioside degradation pathways, no typical clinical phenotypes were observed in the HEXA-/- mouse model, such as nervous system abnormalities, restricted patterns of GM2-ganglioside distribution, and brain Membranous cells in the plastids
.
Therefore, it is necessary to produce an ideal animal model to accurately simulate HEXA ins TATC in TSD patients
.
HDR mediated by the CRISPR-Cas9 system has been used to generate HEXA ins TATC mutations, but low efficiency and high indels hinder its application
.
On July 6, 2021, the joint communication between Li Zhanjun and Lai Liangxue of Jilin University published a research paper entitled "Efficient and precise generation of Tay–Sachs disease model in rabbit by prime editing system" in Cell Discovery.
The research uses guided editing technology ( Prime editing), successfully bred Tay-Sach disease model rabbits, and accurately simulated the occurrence and development of the disease
.
In conclusion, this study verifies the feasibility of the PE system-mediated base insertion, deletion and transformation in rabbits for the first time
.
This ideal new HEXA ins TATC rabbit model will facilitate future research on the pathogenesis of TSD and drug screening
.
Tay-Sach disease (TSD) is an autosomal recessive neurodegenerative disease caused by mutations in the HEXA gene encoding hexose deaminase A (HexA) a subunit, resulting in gangliosides in the brain It accumulates to toxic levels, and usually patients can only survive until two or three years of age
.
The 4 base insertion (1278 ins TATC) of the 11th exon of HEXA gene is the most common mutation
.
Due to the compensatory pathway of ganglioside degradation, HEXA knockout mice cannot accurately mimic the clinical phenotype of Tay-Sach disease
.
The main manifestations are: there is no significant difference in behavior between HEXA-/- mice and WT mice before 1 year old, and the pathology is limited to certain areas of the brain, excluding the olfactory bulb, cerebral cortex, and anterior horns, nor does it show Abnormal phenotype of the nervous system; in addition, the base editor (CBE, ABE) based on the CRISPR system can realize the conversion of CT and AG, but cannot insert or delete genes
.
Therefore, the study used the optimized Prime editing system to find the best pegRNA by optimizing the length of the PBS and RT templates, and screened out that the PBS length is 12 nt and the RT template length is 14 nt as the best combination
.
Further using methods such as microinjection and embryo transfer, HEXA (1278 ins TATC) gene-edited rabbits carrying human homologous mutations were obtained, which verified the high efficiency and effectiveness of the Prime editing system in rabbit genome editing
.
HEXA (1278 ins TATC) gene-edited rabbits show typical symptoms of Tay-Sach disease, such as motor dysfunction, muscle weakness, hind limb buckling, cervical flexion, ataxia and head myoclonic convulsions, which are the pathogenesis of the disease.
And drug screening provides an ideal humanized animal model
.
Qian Yuqiang, a master's student from the College of Animal Science of Jilin University, Zhao Ding, a master's student from the College of Animal Medicine, and Sui Tingting, a postdoctoral faculty member, are the co-first authors of the paper
.
Li Zhanjun and Lai Liangxue are the co-corresponding authors
.
The research was funded by the special project of the National Key Research and Development Program'Stem Cell and Transformation Research'
.
Reference message: https://
It is jointly created by the doctoral team of Tsinghua University, Harvard University, Chinese Academy of Sciences and other units.
The iNature Talent Official Account is now launched, focusing on talent recruitment, academic progress, scientific research information, interested parties can Long press or scan the QR code below to follow us
.
iNatureTay-Sachs disease (TSD) is a progressive neurodegenerative disease due to an autosomal recessive genetic defect in β-hexosaminidase A (HexA)1
.
The four base (TATC) insertion in exon 11 of HEXA (HEXA ins TATC) accounts for 80% of Tay-Sachs disease in Ashkenazi Jewish population
.
However, due to differences in mouse ganglioside degradation pathways, no typical clinical phenotypes were observed in the HEXA-/- mouse model, such as nervous system abnormalities, restricted patterns of GM2-ganglioside distribution, and brain Membranous cells in the plastids
.
Therefore, it is necessary to produce an ideal animal model to accurately simulate HEXA ins TATC in TSD patients
.
HDR mediated by the CRISPR-Cas9 system has been used to generate HEXA ins TATC mutations, but low efficiency and high indels hinder its application
.
On July 6, 2021, the joint communication between Li Zhanjun and Lai Liangxue of Jilin University published a research paper entitled "Efficient and precise generation of Tay–Sachs disease model in rabbit by prime editing system" in Cell Discovery.
The research uses guided editing technology ( Prime editing), successfully bred Tay-Sach disease model rabbits, and accurately simulated the occurrence and development of the disease
.
In conclusion, this study verifies the feasibility of the PE system-mediated base insertion, deletion and transformation in rabbits for the first time
.
This ideal new HEXA ins TATC rabbit model will facilitate future research on the pathogenesis of TSD and drug screening
.
Tay-Sach disease (TSD) is an autosomal recessive neurodegenerative disease caused by mutations in the HEXA gene encoding hexose deaminase A (HexA) a subunit, resulting in gangliosides in the brain It accumulates to toxic levels, and usually patients can only survive until two or three years of age
.
The 4 base insertion (1278 ins TATC) of the 11th exon of HEXA gene is the most common mutation
.
Due to the compensatory pathway of ganglioside degradation, HEXA knockout mice cannot accurately mimic the clinical phenotype of Tay-Sach disease
.
The main manifestations are: there is no significant difference in behavior between HEXA-/- mice and WT mice before 1 year old, and the pathology is limited to certain areas of the brain, excluding the olfactory bulb, cerebral cortex, and anterior horns, nor does it show Abnormal phenotype of the nervous system; in addition, the base editor (CBE, ABE) based on the CRISPR system can realize the conversion of CT and AG, but cannot insert or delete genes
.
Therefore, the study used the optimized Prime editing system to find the best pegRNA by optimizing the length of the PBS and RT templates, and screened out that the PBS length is 12 nt and the RT template length is 14 nt as the best combination
.
Further using methods such as microinjection and embryo transfer, HEXA (1278 ins TATC) gene-edited rabbits carrying human homologous mutations were obtained, which verified the high efficiency and effectiveness of the Prime editing system in rabbit genome editing
.
HEXA (1278 ins TATC) gene-edited rabbits show typical symptoms of Tay-Sach disease, such as motor dysfunction, muscle weakness, hind limb buckling, cervical flexion, ataxia and head myoclonic convulsions, which are the pathogenesis of the disease.
And drug screening provides an ideal humanized animal model
.
Qian Yuqiang, a master's student from the College of Animal Science of Jilin University, Zhao Ding, a master's student from the College of Animal Medicine, and Sui Tingting, a postdoctoral faculty member, are the co-first authors of the paper
.
Li Zhanjun and Lai Liangxue are the co-corresponding authors
.
The research was funded by the special project of the National Key Research and Development Program'Stem Cell and Transformation Research'
.
Reference message: https://
