The potential role of antisense oligodeoxynucleotide therapy for cardiovascular disease

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 year s). Antisense inhibition is being developed for the treatment of hypertensi on, myocardial ischaemia and improved allograft survival in human vascular bypass grafts. We are currently using 2 strategies: (i) antisense oligodeox ynucleotides (AS-ODNs) which are delivered nonvirally and (ii) antisense DN A delivered in viral vectors to inhibit genes associated with vasoconstrict ive properties. It is not necessary to know all the genes involved in hyper tension, 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 (AT(1) ) receptors, angiotensinogen (ATG), angiotensin converting enzyme (ACE) and beta(1) adrenoceptors effectively reduce hypertension in rat models. A sin gle dose is effective for up to one month when delivered with liposomes. No adverse or toxic effects have been detected, and repeated injections are e ffective. For viral delivery, adeno-associated virus (AAV) is used with a c onstruct to include a cytomegalovirus or tissue-specific promoter, antisens e DNA to ATG, ACE or AT(1) receptors and a reporter gene. Results in rats a nd transgenic mice show significant prolonged reduction of hypertension, wi th a single dose administration of AAV-AS. Left ventricular hypertrophy is also reduced by antisense treatment. AS-ODNs to AT(1) receptors, ATG and be ta(1) adrenoceptors provide cardioprotection from the effects of myocardial ischaemia. The AT(1) receptor is more protective than losartan and does no t increase plasma angiotensin as losartan does.