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

#1.1 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 β1-adrenoceptor (β1-adrenergic receptor, β1-AR)-specific mRNA and inhibiting translation of the β1-adrenoceptor mRNA, thereby decreasing the number of β1-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 β1-AR mRNA and alter expression of the mRNA in a host cell.

#1.2 Description of Related Art

#The drawings form part of the present specification and are included to further demonstrate certain aspects of the present invention. The invention may be better understood by reference to one or more of these drawings in combination with the detailed description of specific embodiments presented herein.

#FIG. 1A shows β1-AS-ODN decreased density of β1-ARs but not β2-ARs in cardiac ventricles of SHRs. A1 Time Course of β1-AS-ODN effects on Bmax of β1-ARs ([Circlesolid]) and β2-ARs (∘).

#FIG. 1B shows Bmax of β-ARs 4 days after intravenous injection of saline (solid bar), 1 mg/kg inverted ODN (open bar), or 1 mg/kg β1-AS-ODN (shaded bar). Data represent mean±SEM of each point (n=6). *P<0.01, **P<0.001 vs. saline control.

#4.1 Antisense Oligonucleotides

#The utility of the disclosed compounds and compositions in inhibiting expression of mammalian β1-AR-specific mRNA has been described and demonstrated both in vitro and in vivo by the methods described herein.

#Preferred polynucleotide and oligonucleotide compounds of the present invention specifically bind to an mRNA encoding a mammalian β1-AR polypeptide thereby inhibiting the translation of the mRNA, and concomitant expression of the encoded polypeptide. Highly preferred antisense compounds and compositions are those that specifically bind to the mRNA encoding human β1-AR polypeptide.