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

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 <i>Sim1</i> and <i>Mc4r</i> heterozygous mouse models to rescue their obesity phenotype. Transgenic-based CRISPRa targeting of the <i>Sim1</i> 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 <i>Sim1</i> 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 <i>Sim1</i> and <i>Mc4r</i> haploinsufficient mice. Our results suggest that endogenous gene up-regulation could be a potential strategy to treat altered gene dosage diseases.