SIM1 and obesity due to melanocortin 4 receptor deficiency: For example, activating the Sim1 gene in mice bearing obesity (Sim1 heterozygous knockout mice) to rescue the obesity phenotype (Matharu et al., 2019), up-regulating the Utrn gene in mice (Dmd gene loss-of-function mutant mice) to treat muscular dystrophy (Liao et al., 2017), etc. Low efficiency remains a major roadblock for CRISPRa systems in basic and clinical applications and much effort has been devoted to combating this issue (Konermann et al., 2015; Zhou et al., 2018).