Gene therapy for hypertension

ABSTRACT

Introduction: The control of hypertension and the resulting cardiovascular events is still insufficient. Thus, the search for novel means for blood pressure (BP) reduction remains worth further clinical and research attention. The advances in vector and construct design sketch the use of gene therapy in hypertension.

Areas covered: We have searched for studies using gene therapy in hypertension reporting BP outcomes. We have identified 63 experimental studies demonstrating feasible targeting of the classical and new renin-angiotensin-aldosterone system, β1-adrenergic receptor, NO-cGMP axis, endothelin, natriuretic peptides, kallikrein system, cytochrome P-450 hydroxylase, oncogenes, growth factors, interleukins, angiopoietin-1, adrenomedullin or Klotho in small rodents.

Expert opinion: The usual BP reduction was by 10–30 mmHg for up to several months. Some studies reported target organ damage attenuation or even survival prolongation. However, the concept did not reach the clinical phase, in contrast to other cardiovascular conditions. Increased gene transfection efficacy necessary for a systemic treatment, personalized identification of the implied aetiology from the multifactorial background and evidence from larger mammals are required for gene therapy to compete with the broad spectrum of current therapeutic options in hypertension. Until then, in the field of hypertension, gene modulation will provide a valuable research tool.

KEYWORDS:

• Gene therapy
• arterial hypertension
• vector
• adenovirus
• adeno-associated virus
• RNA interference
• renin-angiotensin-aldosterone system
• natriuretic peptides
• NO-synthase
• kallikrein

Article highlights

• Due to high prevalence and strong impact on morbidity and mortality, the treatment of hypertension remains worth further clinical and research attention.

• As the pharmacotherapy of high blood pressure seems to have reached its (economical) limits and since alternative therapeutic strategies such as device based therapies and vaccination did not meet the desired expectations, gene therapy could be considered as an alternative.

• There is experimental evidence for the feasibility of gene-based anti-hypertensive therapy including target overexpression and silencing.

• Silenced targets include pharmacologically established targets such as the angiotensin II AT1 receptor, angiotensin-converting enzyme, β₁-adrenergic receptor, mineralocorticoid receptor, endothelin-1 as well as experimental targets such as angiotensinogen, (pro)renin receptor, cytochrome P-450 hydroxylase 4A, c-Jun, c-Myc, platelet-derived growth factor and interleukin-6. The most recent studies use RNA interference for silencing.

• The pharmacologically overexpressed targets include the established endothelial NO-synthase and natriuretic peptides and investigational kallikreins, angiotensin-converting enzyme 2, angiotensin II AT2 receptor, cytochrome P-450 hydroxylase 2J3, interleukin-10, angiopoietin-1, adrenomedullin or Klotho.

• Other possible targets that may be applied in the future research of gene therapy options for hypertension include aldosterone synthase, neutral endopeptidase, renin, endothelin-converting enzyme, phosphodiesterases, soluble guanylate cyclase or Mas receptor.

• Up-to-date, the adeno-associated virus, lentivirus or higher adenovirus generation appear to be the most promising vectors. However, further improvement in vector design is necessary to deliver sufficient transfection efficacy required for the treatment of hypertension in clinical setting.

• Currently, for arterial hypertension, the technological options for gene therapy cannot compete with established pharmacotherapy in the clinical setting, no clinical studies have been performed for this disease yet and the available evidence does not extend beyond data from small rodent hypertension models.

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Declaration of interest

No potential conflict of interest was reported by the authors.