| First Author | Matharu N | Year | 2019 |
| Journal | Science | Volume | 363 |
| Issue | 6424 | PubMed ID | 30545847 |
| Mgi Jnum | J:272371 | Mgi Id | MGI:6280633 |
| Doi | 10.1126/science.aau0629 | Citation | Matharu N, et al. (2019) CRISPR-mediated activation of a promoter or enhancer rescues obesity caused by haploinsufficiency. Science 363(6424) |
| abstractText | 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. |
