Current and Future Novel Targets of Gene Therapy for Hypertension

Traditional therapeutic approaches for the treatment and control of hypertension are effective in normalizing blood pressure (BP) in less than a third of patients with hypertension. These pharmacological approaches may have reached a plateau in their effectiveness and newer strategies need to be investigated to not only increase the number of patients achieving BP control, but to find ways to cure the disease instead of just manage it. Since completion of the Human Genome Project and the continuous advancement of gene delivery systems, it is now possible to investigate genetic means for the treatment and possible cure for hypertension. In this review, we discuss potential genetic targeting for treatment of hypertension. There are two generalized gene transfer approaches that have been used successfully for hypertension. One is an induction approach where genes that lower blood pressure are overexpressed. A second method is a reduction approach where products of genes that are known to increase blood pressure are decreased. There are a variety of methods that have been utilized to meet these objectives, such as “knockout” and “ knock-in” animal models, and the use of sense and antisense (AS) technology. This review will focus on the sense and antisense applications, and how this technique is becoming more refined and precise through the targeting of specific tissues, the regulation and induction of components of the system, and use of other newer technologies, such as short interfering RNA (siRNA). Our lab has generally focused on the reduction approach, specifically in the genetic manipulation of components of the renin-angiotensin system (RAS). This system not only modulates BP, but has also been implicated in cardiac hypertrophy and morphology and in insulin resistance, which is highly correlated with hypertension. We will also discuss how new genes can be identified and subsequently serve as targets for the treatment of human hypertension.