CRISPRa corrects haploinsufficient obesity Loss-of-function mutation in one gene copy, termed haploinsufficiency, can lead to insufficient protein levels and result in human disease. Matharu et al. tested whether a CRISPR-based activation system (CRISPRa) could rescue a haploinsufficient phenotype by increasing the gene expression levels of the existing normal copy (see the Perspective by Montefiori and Nobrega). By delivering this system into the mouse hypothalamus using adeno-associated virus, they rescued the obesity phenotype caused by haploinsufficiency of either of two genes known to promote obesity when mutated in mice and humans. These results highlight the translational potential of the CRISPR activation system to treat haploinsufficient disease. Science , this issue p. eaau0629 ; see also p. 231