Note: Many diseases are caused by haploinsufficiency, where one of the two copies of the gene is non functional. In this Science publication, the authors used CRISPRa (CRISPR based activation) to upregulate the expression from the functional copy of the gene Sim1 or Mc4r to rescue the obesity phenotype in mouse models. The CTSI Catalyst project awarded in Spring 2017 to Nadav Ahituv, PhD and Navneet Matharu, PhD (the last and first authors) uses the same CRISPRa approach applied to polycystic kidney disease which is also caused by haploinsufficiency.
Catalyst consultations refined their project plan for the polycystic kidney disease application. Catalyst interns helped them explore other potential diseases with haploinsufficiency and assisted with putting together a target product profile.
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 Sim1 and Mc4rheterozygous mouse models to rescue their obesity phenotype. Transgenic-based CRISPRa targeting of the Sim1 promoter or its distant hypothalamic enhancer upregulated 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-rAAV into the hypothalamus, which led to reversal of the obesity phenotype in Sim1 and Mc4r haploinsufficient mice. Our results suggest that endogenous gene upregulation could be a potential strategy to treat altered gene dosage diseases.