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.

Angiotensin II AT 1A Receptor Antisense Lowers Blood Pressure in Acute 2-Kidney, 1-Clip Hypertension

“…Delivery of the ODN as AS-ODNs liposome mix in 2K1C rats at 30 days after renal artery clipping effectively reduced BP for Ͼ10 days. 13 In our studies of the 2K1C, SBP response to AT 1A R-AS-ODN, the reduction in AT 1A R protein is evidenced by the differential changes in Ang II AT 1 R numbers compared with that of AT 1A -Scr-ODN-treated animals, shown by the quantitative receptor autoradiography. In the thoracic aorta, there was a significant decrease in Ang II AT 1 R binding.…”

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

“…We have established that a single intracardiac injection of a retroviral vector containing ACE-AS causes modest but significant decreases in high BP as seen for the AT 1 R-AS. [35][36][37] (2) Are the antihypertensive effects of the AT 1 R-antisense therapy specific? Our studies demonstrate that AT 1 R-AS expression has no significant effect on the expression of AT 2 receptors 31 and that phenylephrineinduced vascular responses are not altered in the AT 1 R-AStreated rats.…”

Antisense inhibition of secretory and cytosolic phospholipase A2 reduces the mortality in rats with sepsis*

“…Antisense inhibition has been developed for the treatment of diseases resulting from overexpression of genes (19)(20)(21). An antisense oligonucleotide (ODN) is a single-stranded synthetic DNA with a special sequence to hybridize a specific messenger RNA (mRNA).…”

“…(Crit Care Med 2012; 40: 2132-2140) KEY WORDS: antisense oligonucleotide; mortality; phospholipase A 2 ; sepsis hybridization leads to a reduction in the protein level. The specificity and uniqueness of the antisense ODN toward single gene and its efficient cellular uptake and wild distribution among many organs (19)(20)(21) make antisense ODN strategy a most desirable approach for treatment of sepsis because sepsis-induced PLA 2 overexpression takes place in multiple organs. Other advantages include that antisense ODN can be used as a drug, and it has an action that lasts for either days for short-term or weeks for long-term treatments.…”

“…Other advantages include that antisense ODN can be used as a drug, and it has an action that lasts for either days for short-term or weeks for long-term treatments. In addition, antisense ODN is safe and it fails to induce toxic effects such as inflammation and immune responses (19)(20)(21). An additional benefit of employing antisense ODN strategy to correct sepsis-elicited PLA 2 overexpression resides in its ability to "knock-down" rather than "knock-out" the overexpressed gene so that it reduces overactive protein yet permits normal physiology (22).…”