The potential role of antisense oligodeoxynucleotide therapy for cardiovascular disease.

Abstract

Current drugs used in the treatment of cardiovascular disease are effective but compliance is poor and they are short acting (hours or one day). Gene therapy offers a way to produce long-lasting effects (weeks, months or years). Antisense inhibition is being developed for the treatment of hypertension, myocardial ischaemia and improved allograft survival in human vascular bypass grafts. We are currently using 2 strategies: (i) antisense oligodeoxynucleotides (AS-ODNs) which are delivered nonvirally and (ii) 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 (AT1) receptors, angiotensinogen (ATG), angiotensin converting enzyme (ACE) and beta1 adrenoceptors effectively reduce hypertension in rat models. A single dose is effective for up to one month when delivered with liposomes. No adverse or toxic effects have been detected, and repeated injections are effective. For viral delivery, adeno-associated virus (AAV) is used with a construct to include a cytomegalovirus or tissue-specific promoter, antisense DNA to ATG, ACE or AT1 receptors and a reporter gene. Results in rats and transgenic mice show significant prolonged reduction of hypertension, with a single dose administration of AAV-AS. Left ventricular hypertrophy is also reduced by antisense treatment. AS-ODNs to AT1 receptors, ATG and beta1 adrenoceptors provide cardioprotection from the effects of myocardial ischaemia. The AT1 receptor is more protective than losartan and does not increase plasma angiotensin as losartan does.