2. Academic Validation
  3. Leptin gene-targeted editing in ob/ob mouse adipose tissue based on the CRISPR/Cas9 system

Leptin gene-targeted editing in ob/ob mouse adipose tissue based on the CRISPR/Cas9 system

  • J Genet Genomics. 2021 Feb 20;48(2):134-146. doi: 10.1016/j.jgg.2021.01.008.
Lin Zhu 1,  Xiaoyan Yang 2,  Juyi Li 3,  Xiong Jia 4,  Xiangli Bai 5,  Ying Zhao 4,  Wenzhuo Cheng 4,  Meng Shu 4,  Yan Zhu 4,  Si Jin 6
Affiliations

Affiliations

  • 1 Department of Endocrinology, Institute of Geriatric Medicine, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Department of Pediatrics, Tongji Hospital, Tongji Medicine College, Huazhong University of Science and Technology, Wuhan 430030, China.
  • 2 Department 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.
  • 3 Department of Pharmacy, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
  • 4 Department of Endocrinology, Institute of Geriatric Medicine, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
  • 5 Department of Endocrinology, Institute of Geriatric Medicine, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Department of Laboratory Medicine, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
  • 6 Department of Endocrinology, Institute of Geriatric Medicine, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Department 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. Electronic address: [email protected].
PMID: 33931338 DOI: 10.1016/j.jgg.2021.01.008
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% of Leptin 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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