1L1RL-1 as a cardiovascular disease marker and therapeutic target

• US 9,851,362 B2
• Filed: 05/29/2014
• Issued: 12/26/2017
• Est. Priority Date: 05/09/2002
• Status: Active Grant

• Current Assignee: Brigham and Women's Hospital Incorporated
• Original Assignee: Brigham and Women's Hospital
• Inventors: Lee, Richard T.
• Primary Examiner(s): STANFIELD, CHERIE MICHELLE
• Application Number:
  US14/290,465
• Publication Number:
  US 20150153360A1
• Time in Patent Office: 1,307 Days
• CPC Class Codes: A61K 39/00112 Receptors for interferons [IFN]
• 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 9/10 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: G01N 2333/7155 for interleukins [IL]
• CPC Class Codes: G01N 2800/2871 Cerebrovascular disorders, e.g. stroke, cerebral infarct, cerebral haemorrhage, transient ischemic event
• CPC Class Codes: G01N 2800/32 Cardiovascular disorders
• CPC Class Codes: G01N 2800/324 Coronary artery diseases, e.g. angina pectoris, myocardial infarction
• 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 33/6869 Interleukin
• CPC Class Codes: G01N 33/6893 related to diseases not provided for elsewhere
• CPC Class Codes: Y02A 90/10 Information and communication technologies [ICT] supporting adaptation to climate change, e.g. for weather forecasting or climate simulation

Abstract

This invention pertains to methods and compositions for the diagnosis and treatment of cardiovascular conditions. More specifically, the invention relates to isolated molecules that can be used to diagnose and/or treat cardiovascular conditions including cardiac hypertrophy, myocardial infarction, stroke, arteriosclerosis, and heart failure.

Claims

1. A method for predicting outcome of a cardiovascular condition in a subject having or suspected of having a cardiovascular condition and treating the subject, the method comprising:

(a) performing an assay to determine a level of soluble ST2 in a sample comprising blood or serum from a subject having or suspected of having a cardiovascular condition;

(b) comparing the level of soluble ST2 in the sample to a predetermined value specific for predicting outcome of the cardiovascular condition;

(c) identifying a subject having an elevated level of soluble ST2 compared to the predetermined value as having an increased likelihood of a negative outcome of a cardiovascular condition as compared to a subject not having an elevated level of soluble ST2 compared to the predetermined value; and

(d) administering a beta-adrenergic receptor blocker or an angiotensin system inhibitor to the subject identified in (c).

2. The method of claim 1, wherein the cardiovascular condition is selected from the group consisting of cardiac hypertrophy, myocardial infarction, stroke, and heart failure.

3. The method of claim 1, wherein the negative outcome is death, development of congestive heart failure, or worsening of congestive heart failure.

4. The method of claim 3, wherein the death is in-hospital death or death within 30 days.

5. The method of claim 1, wherein the subject has an episode of ischemic discomfort.

6. The method of claim 5, further comprising obtaining a sample from the subject, wherein the sample is obtained from the subject within 12 hours of the episode of ischemic discomfort or 1, 3, 12, or 24 hours after the episode of ischemic discomfort.

7. The method of claim 5, further comprising obtaining a sample from the subject, wherein the sample is obtained from the subject within 6 hours of the episode of ischemic discomfort.

8. The method of claim 1, wherein the subject is without ischemic disease.

9. The method of claim 1, comprising administering a beta-adrenergic receptor blocker to the subject identified in (c).

10. The method of claim 9, wherein the beta-adrenergic receptor blocker is selected from the group consisting of:

atenolol, acebutolol, alprenolol, befunolol, betaxolol, bunitrolol, carteolol, celiprolol, hedroxalol, indenolol, labetalol, levobunolol, mepindolol, methypranol, metindol, metoprolol, metrizoranolol, oxprenolol, pindolol, propranolol, practolol, sotalolnadolol, tiprenolol, tomalolol, timolol, bupranolol, penbutolol, trimepranol, 2-(3-(1,1-dimethylethyl)-amino-2-hydroxypropoxy)-3-pyridenecarbonitril, 1-butylamino-3-(2,5-dichlorophenoxy)-2-propanol, 1-isopropylamino-3-(4-(2-cyclopropylmethoxyethyl) phenoxy)-2-propanol, 3-isopropylamino-1-(7-methylindan-4-yloxy)-2-butanol, 2-(3-t-butylamino-2-hydroxy-propylthio)-4-(5-carbamoyl-2-thienyl)thiazol, and 7-(2-hydroxy-3-t-butylaminopropoxy)phthalide.

11. The method of claim 1, comprising administering an angiotensin system inhibitor to the subject identified in (c).

12. The method of claim 11, wherein the angiotensin system inhibitor is selected from the group consisting of:

angiotensin-converting enzyme (ACE) inhibitors, angiotensin II antagonists, angiotensin II receptor antagonists, agents that activate the catabolism of angiotensin II, and agents that prevent the synthesis of angiotensin I.

13. The method of claim 1, wherein the assay in (a) is performed using an antibody that specifically binds to soluble ST2.

14. A method for predicting outcome of a cardiovascular condition in a subject having or suspected of having a cardiovascular condition and treating the subject, the method comprising:

(a) performing an assay to determine a first level of soluble ST2 in a sample comprising blood or serum obtained at a first time point from a subject having or suspected of having a cardiovascular condition;

(b) performing an assay to determine a second level of soluble ST2 in a sample comprising blood or serum obtained at a second time point from the subject;

(c) comparing the second level of soluble ST2 to the first level of soluble ST2;

(d) identifying a subject having an elevated second level of soluble ST2 compared to the first level of soluble ST2 as having an increased likelihood of a negative outcome of a cardiovascular condition as compared to a subject not having an elevated second level of soluble ST2 compared to the first level of soluble ST2; and

(e) administering a beta-adrenergic receptor blocker or an angiotensin system inhibitor to the subject identified in (d).

15. The method of claim 14, wherein the cardiovascular condition is selected from the group consisting of:

cardiac hypertrophy, myocardial infarction, stroke, and heart failure.

16. The method of claim 14, wherein the subject has had a myocardial infarction.

17. The method of claim 16, wherein the first time point is within 24 hours of the myocardial infarction.

18. The method of claim 14, wherein the second time point is within two weeks after the first time point.

19. The method of claim 14, wherein the negative outcome is death or transplantation.

20. The method of claim 14, wherein the subject is without ischemic disease.

21. The method of claim 14, comprising administering a beta-adrenergic receptor blocker to the subject identified in (d).

22. The method of claim 21, wherein the beta-adrenergic receptor blocker is selected from the group consisting of:

atenolol, acebutolol, alprenolol, befunolol, betaxolol, bunitrolol, carteolol, celiprolol, hedroxalol, indenolol, labetalol, levobunolol, mepindolol, methylpranol, metindol, metoprolol, metrizoranolol, oxprenolol, pindolol, propranolol, practolol, sotalolnadolol, tiprenolol, tomalolol, timolol, bupranolol, penbutolol, trimepranol, 2-(3-(1,1-dimethylethyl)-amino-2-hydroxypropoxy)-3-pyridenecarbonitril, 1-butylamino-3-(2,5-dichlorophenoxy)-2-propanol, 1-isopropylamino-3-(4-(2-cyclopropylmethoxyethyl) phenoxy)-2-propanol, 3-isopropylamino-1-(7-methylindan-4-yloxy)-2-butanol, 2-(3-t-butylamino-2-hydroxy-propylthio)-4-(5-carbamoyl-2-thienyl)thiazol, and 7-(2-hydroxy-3-t-butylaminopropoxy)phthalide.

23. The method of claim 14, comprising administering an angiotensin system inhibitor to the subject identified in (d).

24. The method of claim 23, wherein the angiotensin system inhibitor is selected from the group consisting of:

angiotensin-converting enzyme (ACE) inhibitors, angiotensin II antagonists, angiotensin II receptor antagonists, agents that activate the catabolism of angiotensin II, and agents that prevent the synthesis of angiotensin I.

25. The method of claim 14, wherein the assay in (a) and the assay in (b) are performed using an antibody that specifically binds to soluble ST2.