[1] Gene therapy for hypertension: The preclinical data

Abstract

Abstract-Despite several drugs for the treatment of hypertension, there are many patients with poorly controlled high blood pressure. This is partly because all of the available drugs are short-lasting (Յ24 hours), have side effects, and are not highly specific. Gene therapy offers a possibility of producing longer-lasting effects with precise specificity based on the genetic design. Preclinical studies on gene therapy for hypertension have taken 2 approaches. Chao et al have performed extensive studies on gene transfer to increase vasodilator proteins. They have transferred kallikrein, atrial natriuretic peptide, adrenomedullin, and endothelin NO synthase into different rat models. Their results show that blood pressure can be lowered for 3 to 12 weeks with the expression of these genes. The antisense approach, which we began by targeting angiotensinogen and the angiotensin type 1 (AT 1 ) receptor, has now been tested independently by several different groups in multiple models of hypertension. Other genes targeted include the ␤ 1 -adrenoceptor, thyrotropinreleasing hormone, angiotensin gene-activating elements, carboxypeptidase Y, c-fos, and CYP4A1. There have been 2 methods of delivering antisense: one is by oligodeoxynucleotides, and the other is with full-length DNA in viral vectors.All the studies show a decrease in blood pressure lasting several days to weeks or months. Oligos are safe and nontoxic and could be delivered orally or eventually by skin patches. Systemic delivery of recombinant adeno-associated virus with DNA antisense to AT 1 receptors in adult rodents decreases hypertension for up to 6 months. We conclude that there is sufficient preclinical data to give serious consideration to phase I trials for testing some of the antisense oligodeoxynucleotides, although testing the viral vectors needs much more work.

AAV delivery of mineralocorticoid receptor shRNA prevents progression of cold-induced hypertension and attenuates renal damage

“…40,41 Nevertheless, a virus control (AAV.Control-shRNA) and a virus-free control (PBS) were used to exclude possibilities that may complicate interpretation of the experimental data due to the employment of viral vector. Control-shRNA is scrambled in sequence and has been proven, by BD Clontech (Palo Alto, CA, USA), not to interact with any known gene sequence.…”

“…It is known that the AAV vector can deliver target genes to the nuclei of cells, where the target gene then integrates into the host genome. 40,42 These features make it possible to develop permanent gene therapy for humans using AAV vector. In the present study, we employed AAV-2, which has a high selective affinity, to renal tubule epithelial cells.…”

Recombinant adeno-associated virus-mediated kallikrein gene therapy reduces hypertension and attenuates its cardiovascular injuries

“…[1][2][3] Clinical trials conducted in the last two decades have demonstrated that a reduction in blood pressure of 10/ 5 mmHg will result in the decrease in stroke mortality by 40% and coronary heart disease by 20%, regardless of the classes of antihypertensive drugs prescribed. [1][2][3] However, the ratio of goal blood pressure control is very low, especially in the developing countries (about 4%), because current drugs, although effective, have poor compliance, are expensive and short-lasting (hours or one day). Gene therapy may have the potential to solve these problems and provide an effective and stable control of blood pressure for hypertensive patients.…”

“…7,[19][20][21] Gene therapy for hypertension is a viable strategy. [1][2][3] The application of kallikrein gene therapy to reduce blood pressure has been tested in several hypertensive rat models, and the results showed that the injection of various kallikrein gene constructs with adenovirus or plasmids caused a significant reduction in systemic blood pressure in SHRs, one-clip Goldblatt hypertensive rats and Dahl-salt-sensitive hypertensive rats. [22][23][24][25][26][27] All those studies, however, were performed using transient expression vectors and provided short-term control of blood pressure (a few weeks), a duration not meeting the requirement for clinical therapy of hypertension.…”

Recombinant adeno-associated virus-mediated human kallikrein gene therapy protects against hypertensive target organ injuries through inhibiting cell apoptosis

“…Gene therapy may provide long-term control of blood pressure for hypertensive patients [2] . Recombinant adeno-associated virus (rAAV) is an appealing vector for gene therapy protocols [3] , possibly mediating stable transduction and long-term expression of target genes in vivo.…”