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Science. 2019 Jan 18;363(6424). pii: eaau0629. doi: 10.1126/science.aau0629. Epub 2018 Dec 13.

CRISPR-mediated activation of a promoter or enhancer rescues obesity caused by haploinsufficiency.

Author information

1
Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA 94158, USA.
2
Institute for Human Genetics, University of California San Francisco, San Francisco, CA 94158, USA.
3
Doctor of Philosophy Program in Medical Sciences, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
4
Diabetes Center, University of California San Francisco, San Francisco, CA 94143, USA.
5
Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA 94158, USA. nadav.ahituv@ucsf.edu.

Abstract

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.

PMID:
30545847
PMCID:
PMC6570489
DOI:
10.1126/science.aau0629
[Indexed for MEDLINE]
Free PMC Article

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