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

• DOI: 10.1126/science.aau0629
• Publication Date: 2018-12-14T00:19:26Z
• Authors: Navneet Matharu; Sawitree Rattanas...; Serena Tamura; Lenka Maliskova; Yi Wang; Adelaide Bernard; Aaron Hardin; Walter L. Eckalbar; Christian Vaisse; Nadav Ahituv
• Keywords: Haploinsufficiency

A wide range of human diseases result from haploinsufficiency, where the function one two gene copies is lost. Here, we targeted remaining functional copy a haploinsufficient using CRISPR-mediated activation (CRISPRa) in Sim1 and Mc4r heterozygous mouse models to rescue their obesity phenotype. Transgenic-based CRISPRa targeting promoter or its distant hypothalamic enhancer up-regulated expression endogenous allele tissue-specific manner, rescuing phenotype mice. To evaluate therapeutic potential CRISPRa, injected CRISPRa-recombinant adeno-associated virus into hypothalamus, which led reversal Our results suggest that up-regulation could be strategy treat altered dosage diseases.