Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2000-07-11
2002-12-03
McGarry, Sean (Department: 1635)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C435S006120, C435S375000, C435S377000, C435S320100, C536S024100, C536S024500, C536S023100
Reexamination Certificate
active
06489307
ABSTRACT:
1.0 BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates generally to the fields of cardiovascular disease and hypertension. More particularly, it concerns antisense oligonucleotide compositions and methods that are useful for reducing hypertension, cardiac hypertrophy, and myocardial ischemia in animals, particularly in mammals such as humans. Specifically, the invention provides antisense oligonucleotide and polynucleotide compositions capable of binding to &bgr;
1
-adrenoceptor (&bgr;
1
-adrenergic receptor, &bgr;
1
-AR)-specific mRNA and inhibiting translation of the &bgr;
1
-adrenoceptor mRNA, thereby decreasing the number of &bgr;
1
-AR polypeptides in cells capable of expressing this mRNA. Disclosed are antisense oligonucleotide and peptide nucleic acid compositions, pharmaceutical formulations thereof, and vectors encoding antisense oligonucleotides that specifically bind &bgr;
1
-AR mRNA and alter expression of the mRNA in a host cell.
2. Description of Related Art
1.2.1 Hypertension
Hypertension is the result of increased arterial resistance to blood flow and left untreated can lead to various pathological consequences. Hypertension affects approximately 40 million people in the United States. Heart attack (Nicholls et al., 1998), kidney damage (Agodoa, 1998), stroke (Chamorro et al., 1998) and loss of vision (Satllworth and Waldron, 1997) are typical conditions that result from high blood pressure. When blood vessels are subjected to high pressure for extended periods of time, they respond by thickening, vasospasm, and internal build-up of lipids and plaques, a condition known as arteriosclerosis. Arteriosclerosis further causes a decreased blood flow to the kidneys, which respond by releasing the protease renin. An overactive renin-angiotensin system is often implicated in the development of hypertension and cardiovascular disease (Nicholls et al., 1998).
Hypertension is often called the “silent killer,” since half of the population afflicted with high blood pressure are unaware of the condition. Thus, an initial step in combating hypertension is early detection. Following diagnosis, actions must be taken to control the disorder.
1.2.2 Treatment of Hypertension
Currently, four major categories of hypertensive drugs are administered to treat high blood pressure: (1) Diuretics, typically the drug of choice when the abnormal blood pressure is not very high, increase the rate at which the body eliminates urine and salt, resulting in decreased blood pressure by reducing volume (Moser, 1998); (2) &bgr;-adrenergic blockers (&bgr;-blockers), typically prescribed in combination with diuretics, lower blood pressure and heart rate (Rodgers, 1998); (3) Calcium channel blockers work by preventing the entry of calcium into cells, which reduces vasoconstriction (Rosenthal, 1993); (4) angiotensin converting enzyme (ACE) inhibitors prevent the narrowing and constriction of blood vessels by blocking the production of the vasoconstrictive peptide angiotensin II (AT-II), a product of ACE (Rosenthal, 1993).
Unfortunately, the short lasting effects of these drugs often require multiple, even daily doses to be therapeutically effective. Poor compliance is a major problem with drug regimens and can lead to a hypertensive crisis if the drug is not taken as scheduled.
The sympathetic nervous system plays a crucial role in the regulation of blood pressure (BP), mainly through activating &agr;- and &bgr;-adrenergic receptors &bgr;
1
-ARs) in the effector organs, including heart, kidney, and blood vessels. Adrenergic-blocking agents, especially &bgr;-blockers, are commonly used in the treatment of hypertension, ischemic heart disease, and arrhythmia (reviewed in Sproat and Lopez, 1991). However, &bgr;-blockers cause several side effects, which are usually associated with their central nervous system (CNS) reaction (e.g., sleep disturbance, depression, impotence, dizziness and fatigue) and &bgr;
2
-adrenergic antagonistic activity (e.g., increase in peripheral vascular resistance, worsening of asthma symptoms). In addition, because of their short half-life (3 to 10 hrs), &bgr;-blockers must be taken daily to be effective. Because a cardiovascular disease such as hypertension is a life-lone disorder, longer-lasting treatment without side effects would be desirable.
Although the precise mechanism underlying the antihypertensive effects of &bgr;-blockers remains unclear, it is generally accepted that they antagonize the &bgr;
1
-AR activity in heart and kidney, decreasing cardiac output and plasma renin activity (Sproat and Lopez, 1991). A new approach to &bgr;
1
-blockade has been designed that reduces the number of receptors. Antisense oligonucleotides (AS-ODN) or antisense DNA designed specifically against B
1
-ARs might represent a new class of &bgr;-blockers. Antisense techniques, through a number of mechanisms (Phillips et al., 1997), can effectively downregulate the expression of target proteins. Clinical trials using antisense in targeting AIDS (Akhtar and Rossi, 1996), cancer (Dachs et al., 1997), and other genetic and acquired diseases (Yla, 1997) indicate their potential clinical usefulness. The antisense approach has several potential advantages over &bgr;-blockers. First, the specificity of AS-ODNs is based on DNA sequence. Second, AS-ODNs do not have direct CNS effects, because of the negligible transport of these highly polar molecules through the blood-brain barrier (Agrawal et al., 1991). Third, antisense elements tested in different systems produce long-term effects after single treatment (Gyurko et al., 1997). This prolonged effect can be attributed to 2 features of AS-ODN. One is the extended half-life of chemically modified ODN. The half-life 15-20-mer phosphorothioated ODN is 20 to 50 hrs in rats and mice after intravenous injection (Iversen, 1991; Zhang et al., 1995). The other is associated with the nature of antisense inhibition, which provides a delayed yet prolonged blockade of target proteins distinct from the direct competitive antagonists currently available.
1.2.3 &bgr;
1
-Adrenoceptors
&bgr;
1
-ARs, which are distributed in the heart, kidney and blood vessels, play a role in the physiological control of blood pressure. For many years &bgr;-blocker drugs have been used for the treatment of hypertension through a regimen of daily dosing. The mechanism of control of blood pressure is not precisely known but the value of beta-blockers in hypertension control has been underscored by the reports of the Joint National Committee on High Blood Pressure recommending &bgr;-blockers as the first line of defense in the treatment of hypertension. Current &bgr;-blocker drugs, however, have certain disadvantages, including: (1) they have to be taken daily, or twice a day and compliance is a problem; (2) they have central effects, leading to psychological changes that contribute to the problem of patient compliance; and (3) many of the &bgr;-blockers now available are not specific for &bgr;
1
-ARs and, therefore, can have untoward side effects.
1.3 Deficiences in the Prior Art
As can be understood from the above, there remains a need for an effective &bgr;
1
-AR blocker that is highly specific, nontoxic, produces few side effects and does not cross the blood brain barrier to produce psychological changes. Also, a &bgr;-blocker that would last several days or weeks would allow patients more flexibility in the regimen of drug dosage by taking drugs infrequently. Thus, the need exists for an effective treatment of cardiac deficiencies (including hypertension, hypertrophy, ischemias, and the like) that circumvents the toxic side effects of existing therapies and provides more specific &bgr;
1
-AR inhibition with longer acting effects for improved patient compliance. In addition, methods for delivery of antisense oligonucleotides and polynucleotides to a host cell, and in particular, non-invasive administration of specific antisense constructs to a mammal such as a human subject is particularly desirable.
2.0 SUMMARY OF THE INVENTION
The present invention
Phillips M. Ian
Zhang Yuan
McGarry Sean
University of Florida
Williams Morgan & Amerson P.C.
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