期刊
SCIENCE
卷 363, 期 6424, 页码 246-+出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aau0629
关键词
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资金
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [1R01DK090382]
- UCSF Nutrition Obesity Research Center - National Institutes of Health [P30DK098722]
- UCSF School of Pharmacy 2017 Mary Anne Koda-Kimble Seed Award for Innovation
- National Human Genome Research Institute (NHGRI)
- Division of Cancer Prevention, National Cancer Institute [1R01CA197139]
- National Institute of Mental Health [1R01MH109907]
- National Institute of Child and Human Development [1P01HD084387]
- NHGRI [1UM1HG009408]
- UCSF Catalyst Program
- Royal Golden Jubilee Ph.D. Program [PHD/0071/2554]
- NIDDK [R01DK106404, R01 DK60540-09]
- National Institute of General Medical Sciences IRACDA award [K12GM081266]
- American Diabetes Association Mentor Based Award [7-12-MN-79]
A wide range of human diseases result from haploinsufficiency, where the function of one of the two gene copies is lost. Here, we targeted the remaining functional copy of a haploinsufficient gene using CRISPR-mediated activation (CRISPRa) in Sim1 and Mc4r heterozygous mouse models to rescue their obesity phenotype. Transgenic-based CRISPRa targeting of the Sim1 promoter or its distant hypothalamic enhancer up-regulated its expression from the endogenous functional allele in a tissue-specific manner, rescuing the obesity phenotype in Sim1 heterozygous mice. To evaluate the therapeutic potential of CRISPRa, we injected CRISPRa-recombinant adeno-associated virus into the hypothalamus, which led to reversal of the obesity phenotype in Sim1 and Mc4r haploinsufficient mice. Our results suggest that endogenous gene up-regulation could be a potential strategy to treat altered gene dosage diseases.
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