Xiaoyan Yang
Juyi Li
Xiong Jia
Xiangli Bai
Ying Zhao
Wenzhuo Cheng
Meng Shu
Yan Zhu
Si Jin
aDepartment of Endocrinology, Institute of Geriatric Medicine, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
bDepartment of Pediatrics, Tongji Hospital, Tongji Medicine College, Huazhong University of Science and Technology, Wuhan 430030, China
cDepartment of Pharmacology, Hubei Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
dDepartment of Pharmacy, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
eDepartment of Laboratory Medicine, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
More InformationCorresponding author: E-mail address: Jinsi@hust.edu.cn (Si Jin)
Received Date: 2020-10-27
Accepted Date:2021-01-28
Rev Recd Date:2021-01-25
Available Online: 2021-03-30 Publish Date:2021-02-20
Abstract
Abstract
Gene therapy has become the most effective treatment for monogenic diseases. Congenital LEPTIN deficiency is a rare autosomal recessive monogenic obesity syndrome caused by mutations in the Leptin gene. Ob/ob mouse is a monogenic obesity model, which carries a homozygous point mutation of C to T in Exon 2 of the Leptin gene. Here, we attempted to edit the mutated Leptin gene in ob/ob mice preadipocytes and inguinal adipose tissues using CRISPR/Cas9 to correct the C to T mutation and restore the production of LEPTIN protein by adipocytes. The edited preadipocytes exhibit a correction of 5.5% ofLeptin alleles and produce normal LEPTIN protein when differentiated into mature adipocytes. The ob/ob mice display correction of 1.67% of Leptin alleles, which is sufficient to restore the production and physiological functions of LEPTIN protein, such as suppressing appetite and alleviating insulin resistance. Our study suggests CRISPR/Cas9-mediated in situ genome editing as a feasible therapeutic strategy for human monogenic diseases, and paves the way for further research on efficient delivery system in potential future clinical application.Keywords: CRISPR/Cas9,
Gene editing,
Leptin,
Monogenetic disease,
Obesity
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