Methods for Treatment with Bucindolol Based on Genetic Targeting

• US 20080227844A1
• Filed: 08/13/2007
• Published: 09/18/2008
• Est. Priority Date: 09/14/2004
• Status: Active Grant

• Current Assignee: The Board of Regents of the University of Colorado (University of Colorado System)
• Original Assignee: The Board of Regents of the University of Colorado (University of Colorado System)
• Inventors: Bristow, Michael, Liggett, Stephen B.
• Granted Patent: US 8,093,286 B2
• Time in Patent Office: Days
• US Class Current: 514/415
• CPC Class Codes: A61B 5/021 Measuring pressure in heart or blood vessels A61B5/0205 takes precedence
• CPC Class Codes: A61P 25/06 Antimigraine agents
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/04 Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/06 Antiarrhythmics
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C12Q 1/6883 for diseases caused by alterations of genetic material
• CPC Class Codes: C12Q 2600/106 Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
• CPC Class Codes: C12Q 2600/156 Polymorphic or mutational markers
• CPC Class Codes: C12Q 2600/158 Expression markers
• CPC Class Codes: C12Q 2600/172 Haplotypes
• CPC Class Codes: G01N 2800/325 Heart failure or cardiac arrest, e.g. cardiomyopathy, congestive heart failure
• CPC Class Codes: G01N 2800/52 Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
• CPC Class Codes: G01N 33/5041 involving analysis of members of signalling pathways
• CPC Class Codes: G01N 33/6887 from muscle, cartilage or connective tissue

Abstract

The present invention concerns the use of methods for evaluating bucindolol treatment for a patient, particularly one with heart failure. It concerns methods for determining whether to administer or prescribe bucindolol to a patient based on whether the patient is homozygous for the Arg 389 polymorphism in the β1-adrenergic receptor (AR).

Claims

1-94. -94. (canceled)

95. A method for evaluating bucindolol treatment for a patient comprising:

obtaining sequence information regarding a polymorphism in a β

₁ adrenergic receptor (β

₁AR) gene of the patient, wherein the information is predictive of bucindolol efficacy or adverse events in the patient.

96. The method of claim 95, wherein the sequence information regarding a polymorphism in a β

₁AR gene comprises either (i) the sequence at nucleotide position 1165 in the coding sequence in one or both of the patient'"'"'s β

₁AR alleles or (ii) the amino acid at position 389 of the patient'"'"'s β

₁AR proteins, wherein the patient is being considered for treatment with bucindolol.

97. The method of claim 96, wherein the sequence information is the sequence at nucleotide position 1165 in the coding sequences in one or both the patient'"'"'s β

₁AR alleles.

98. The method of claim 96, wherein the sequence information is the sequence in the coding sequences in both of the patient'"'"'s β

₁AR alleles.

99. The method of claim 96, wherein the sequence information is the amino acid at position 389 in the patient'"'"'s β

₁AR proteins.

100. The method of claim 96, further comprising obtaining a biological sample from the patient.

101. The method of claim 100, wherein the biological sample is a blood or buccal sample.

102. The method of claim 96, further comprising obtaining a patient history regarding (i) and/or (ii).

103. The method of claim 96, wherein obtaining sequence information regarding (i) and/or (ii) involves determining (i) and/or (ii).

104. The method of claim 103, wherein the sequence at nucleotide position 1165 in the coding sequences of one or both of the patient'"'"'s β

₁AR alleles is determined.

105. The method of claim 104, wherein determining the sequence comprises chain terminating sequencing, restriction digestion, allele-specific polymerase reaction, single-stranded conformational polymorphism analysis, genetic bit analysis, temperature gradient gel electrophoresis, denaturing gradient gel electrophoresis, or ligase chain reaction.

106. The method of claim 104, wherein the patient is determined to have a cytosine at position 1165 in the coding sequences of one or both β

₁AR alleles.

107. The method of claim 106, wherein the patient is determined to have a cytosine at position 1165 in the coding sequence of one β

₁AR allele and a guanine at position 1165 in the coding sequence of the other β

₁AR allele.

108. The method of claim 103, wherein the amino acid at position 389 of the patient'"'"'s β

₁AR proteins is determined.

109. The method of claim 108, wherein determining the amino acid comprises using an antibody, high pressure liquid chromatography, or mass spectroscopy.

110. The method of claim 108, wherein the patient is determined to have arginine, glycine, or both at position 389 in the β

₁AR proteins.

111. The method of claim 108, wherein the patient is determined to have glycine at position 389 in the β

₁AR proteins.

112. The method of claim 108, wherein the patient is determined to have arginine at position 389 in some β

₁AR proteins and a glycine in other β

₁AR proteins.

113. The method of claim 95, further comprising determining the sequence information and preparing a report containing the results of the determination.

114. The method of claim 95, wherein the patient has symptoms of or has been diagnosed with a medical condition comprising heart failure, dilated cardiomyopathy, ischemic heart disease, pheochromocytoma, migraines, cardiac arrhythmias, hypertension or an anxiety disorder.

115. The method of claim 114, wherein the patient has symptoms of or has been diagnosed with ischemic heart disease.

116. The method of claim 115, wherein the ischemic heart disease is angina and/or a myocardial infarction.

117. The method of claim 114, wherein the patient has symptoms of or has been diagnosed with heart failure.

118. The method of claim 117, wherein the heart failure is advanced heart failure.

119. The method of claim 118, wherein the advanced heart failure is NYHA class III or IV heart failure.

120. The method of claim 96, further comprising prescribing or administering bucindolol to the patient after obtaining sequence information about (i) or (ii), wherein the patient has the Arg389/Arg389 genotype.

121. The method of claim 96, further comprising prescribing or administering to the patient a β

-blocker that is not bucindolol after obtaining sequence information about either (i) or (ii), wherein the patient does not have the Arg389/Arg389 genotype.

122. A method for evaluating whether a heart failure patient will respond positively to bucindolol comprising:

a) obtaining information indicating the presence of a polymorphism at the coding position 1165 in the coding sequence of one or both β

₁AR alleles of the patient or the presence of a polymorphism at the amino acid at position 389 of the β

₁AR protein; and

b) prescribing or administering bucindolol, if the patient has a β

₁AR Arg389/Arg389 genotype;

or not prescribing or administering bucindolol if the patient does not have a β

₁AR Arg389/Arg389 genotype.

123. A method for treating a patient comprising:

a) obtaining information indicating whether the patient has homozygous Arg389 genotype at β

₁AR; and

b) either prescribing bucindolol therapy for the patient wherein the patient'"'"'s genotype is homozygous Arg389 at the β

₁AR protein or not prescribing bucindolol for the patient wherein the patient'"'"'s genotype is not homozygous Arg389 at the β

₁AR protein.