Somatic gene therapy for hypertension

Abstract

Gene therapy for hypertension is needed for the next generation of antihypertensive drugs. Current drugs, although effective, have poor compliance, are expensive and short-lasting (hours or one day). Gene therapy offers a way to produce long-lasting antihypertensive effects (weeks, months or years). We are currently using two strategies: a) antisense oligodeoxynucleotides (AS-ODN) and b) antisense DNA delivered in viral vectors to inhibit genes associated with vasoconstrictive properties. It is not necessary to know all the genes involved in hypertension, since many years of experience with drugs show which genes need to be controlled. AS-ODN are short, single-stranded DNA that can be injected in naked form or in liposomes. AS-ODN, targeted to angiotensin type 1 receptors (AT 1 -R), angiotensinogen (AGT), angiotensin converting enzyme, and ß1-adrenergic receptors effectively reduce hypertension in rat models (SHR, 2K-1C) and coldinduced hypertension. A single dose is effective up to one month when delivered with liposomes. No side effects or toxic effects have been detected, and repeated injections can be given. For the vector, adenoassociated virus (AAV) is used with a construct to include a CMV promoter, antisense DNA to AGT or AT 1 -R and a reporter gene. Results in SHR demonstrate reduction and slowing of development of hypertension, with a single dose administration. Left ventricular hypertrophy is also reduced by AAV-AGT-AS treatment. Double transgenic mice (human renin plus human AGT) with high angiotensin II causing high blood pressure, treated with AAV-AT 1 -R-AS, show a normalization of blood pressure for over six months with a single injection of vector. We conclude that ODNs will probably be developed first because they can be treated like drugs for the treatment of hypertension with long-term effects. Viral vector delivery needs more engineering to be certain of its safety, but one day may be used for a very prolonged control of blood pressure.

Genetic targeting for cardiovascular therapeutics: are we near the summit or just beginning the climb?

“…The studies so far have established that genetic targeting of the RAS prevents hypertension for life in the SHR. They are consistent with data from the other groups (89,90). Thus it appears that the strategy is technically feasible and innovative and could constitute the basis for further developments.…”

The Future of Hypertension Therapy: Sense, Antisense, or Nonsense?

“…Intracardiac administration of retroviral or AAV vector containing AT 1 R-AS into adult SHR or double-transgenic mice results in a significant decrease in BP that was maintained for weeks. 9,10,44 This was accompanied with reversal of the increased vasoreactivity and gain of endothelial function in renal resistance arterioles. Chao and associates 45,46 have used the "sense" approach with the kallikrein and ANP genes to reverse hypertension transiently through the use of adenoviral vectors.…”

20 Years of Hypertension Research using Genetically Modified Animals: No Clinically Promising Approaches in Sight

“…Despite positive findings in preclinical studies, gene therapy has not yet gained clinical relevance for the treatment of hypertension (Gelband et al, 2000;Phillips, 2000;Phillips et al, 2000;Khurana et al, 2001;Phillips, 2001;Baker, 2002;Hirooka et al, 2003;Veerasingham et al, 2004;Melo et al, 2004). the analysed publications mention or describe the use of vectors for therapeutic gene transfer that are already in clinical use.…”