Antisense compositions targeted to beta1-adrenoceptor-specific mRNA and methods of use

Abstract

Disclosed are antisense oligonucleotide, polynucleotide, and peptide nucleic acid compounds that specifically bind to mammalian mRNA encoding a beta1-adrenoceptor polypeptide and that are useful in the control and / or treatment of cardiac dysfunction, hypertension, hypertrophy, myocardial ischemia, and other cardiovascular diseases in an affected mammal, and preferably, in a human subject. The antisense compounds disclosed herein, and pharmaceutical formulations thereof, provide sustained control of beta1-adrenoceptor expression over prolonged periods, and achieve therapeutic effects from as little as a single dose. Administration of these antisense compositions to approved animal models resulted in a decrease in blood pressure, but no significant change in heart rate. Use of such antisense compositions in the reduction of beta1-adrenoceptor polypeptides in a host cell expressing beta1-adrenoceptor-specific mRNA, and in the preparation of medicaments for treating human and animal diseases, and in particular, hypertension and other cardiac dysfunction is also disclosed.

Description

[0001] The present application is a continuation-in-part of U.S. patent application Ser. No. 09 / 152,717 filed Sep. 14, 1998, and issued Jul. 11, 2000 as U.S. Pat. No. 6,087,343, and PCT International patent application Serial No. PCT / US99 / 21007, filed, Sep. 14, 1999, and published Mar. 23, 2000 as WO 00 / 15783, the entire contents of each of which is specifically incorporated herein by reference in its entirety without disclaimer.1.0 BACKGROUND OF THE INVENTION[0003] 1.1 Field of the Invention[0004] 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 .beta..sub.1-adrenoceptor (.beta..sub.1-adrenergic recep...

AI Technical Summary

Benefits of technology

The antisense compounds effectively reduce β1-adrenoceptor activity, offering a more specific and prolonged therapeutic benefit for hypertension and related cardiovascular conditions with reduced side effects and improved patient compliance.

Problems solved by technology

Hypertension is the result of increased arterial resistance to blood flow and left untreated can lead to various pathological consequences.

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.

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).

Current .beta.-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 .beta.-blockers now available are not specific for .beta..sub.1-ARs and, therefore, can have untoward side effects.

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