Gene therapy for hypertension: sense and antisense strategies

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: antisense oligodeoxynucleotides (AS-ODN), andantisense 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-ODNs are short, single-stranded DNA that can be injected in naked form or in liposomes. AS-ODNs, targeted to AT1 receptors (AT1R), angiotensinogen (AGT), angiotensin converting enzyme (ACE) and β1-adrenergic receptors effectively reduce hypertension in rat models (SHR, 2K-1C and cold-induced) hypertension. The effects can last 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, adeno-associated virus (AAV) is used with a construct to include a CMV promoter, antisense DNA to AGT or AT1R and a reporter gene. Results in SHR demonstrate reduction and slowing of hypertension development with a single dose administration. Left ventricular hypertrophy is also reduced by AAV-AS-AGT treatment. Double transgenic mice (human renin plus human AGT) with high angiotensin II (Ang II) causing high blood pressure, treated with AAV-AT1R-AS, show a normalisation of blood pressure for over 6 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.