Abstract 15555: Potential Cure for Hypertension? The Effect of Crispr Genome Editing

Abstract

Hypertension is recognized as one of the largest contributors to the global burden of disease. Unfortunately, for the majority of patients, hypertension is poorly controlled due, in part, to poor medical compliance resulting from the need to take one or more drugs, often several times daily. An ideal therapy would be administered a single time but yield long-term blood pressure control. Under the appropriate condition, we hypothesize that this modality could potentially lead to a cure for hypertension. In this study, we investigated whether that sustained, and possibly life-long, reductions in blood pressure could be achieved via Crispr-Cas9 mediated disruption of a key gene in the RAAS, Angiotensinogen (AGT). In vitro, we demonstrated that expression of Crispr-Cas9 system in the BRL 3A rat liver cell line led to a significant reduction in AGT protein levels (75% reduction, N=3, P<0.01). Delivery of the Crispr-Cas9 system into the liver via systemic delivery of the hepatocyte-targeting AAV8 reduced both AGT mRNA (70% reduction, N=5, P<0.01) and circulating AGT protein (50% reduction, N=5, P<0.01) and Ang II levels (33% reduction, n=5, P<0.01). In the SHR model of hypertension, Crispr-Cas9 mediated loss of AGT expression reduced systolic blood pressure in adult animals with established hypertension (30-35mmHg decrease in both females and males, N=12, P<0.001). Importantly, AGT gene disruption also prevented the spontaneous development of hypertension in young pre-hypertensive SHR (SHR control: 55-60mmHg increase in systolic blood pressure both female and male SHR; SHR plus Crispr-Cas9: 30-33 mmHg increase. N=12. P<0.001). Importantly, in all the models studied, reductions in blood pressure were sustained for at least 4 months. Importantly, the partial disruption of the hepatic AGT gene was sufficient to control hypertension but did not block the renin-angiotensin response to cardiovascular stress such as sodium depletion. In summary, we have demonstrated that targeting the Crispr-Cas9 system to RAAS reduces blood pressure and may be a potential therapy to achieve safe and sustained, possibly life-long, control of hypertension and this approach maybe a cure for hypertension.