NOTCH inhibition in the treatment or prevention of atherosclerosis

• US 20090175849A1
• Filed: 03/02/2007
• Published: 07/09/2009
• Est. Priority Date: 03/07/2006
• Status: Active Grant

• Current Assignee: Brigham and Women's Hospital Incorporated
• Original Assignee: Brigham and Women's Hospital Incorporated
• Inventors: Aikawa, Masanori
• Granted Patent: US 8,133,857 B2
• Time in Patent Office: Days
• US Class Current: 424/130.100
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 39/395 Antibodies agglutinins A61K38/36 ; as drug carriers A61K47/50; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
• CPC Class Codes: A61K 39/39533 against materials from animals
• CPC Class Codes: A61K 48/00 Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
• 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: C07K 14/705 Receptors; Cell surface antigens; Cell surface determinants tumour specific antigens C07K14/4748
• CPC Class Codes: C07K 16/18 against material from animals or humans
• CPC Class Codes: C07K 16/22 against growth factors ; against growth regulators
• CPC Class Codes: C07K 2317/76 Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Abstract

The present invention is directed to methods of treating or preventing atherosclerosis and other cardiovascular diseases by administering agents that inhibit or modulate the NOTCH signaling pathway. In addition, the invention encompasses methods for assaying compounds for their ability to treat atherosclerosis based upon their effects on NOTCH signaling, and for measuring levels of amount, function, or activity of NOTCH pathway components in biological samples.

Claims

1. A method of treating or preventing cardiovascular disease in a patient, comprising administering systemically or locally to said patient a therapeutically effective amount of a compound that inhibits or modulates the NOTCH signaling pathway.

2. The method of claim 1, wherein said cardiovascular disease is selected from the group consisting of:

atherosclerosis;

heart attack;

restenosis after coronary intervention;

failure of vein grafts for coronary bypass surgery or hemodialysis shunts;

vasculitis;

cardiac damage following acute myocardial infarction;

chronic heart failure;

arterial or valvular calcification; and

stroke.

3. The method of claim 1, wherein said compound is a gamma-secretase inhibitor.

4. The method of claim 1, wherein said compound inhibits or modulates a biological process associated with or regulated by the NOTCH pathway, said biological process being selected from the group consisting of:

the binding of a ligand to a Notch receptor;

expression, function, or activity of any NOTCH pathway component;

Notch receptor trafficking or cleavage;

cleavage or endocytosis of a Notch ligand;

activation of macrophages or other cell types responsible for cardiovascular diseases; and

alteration of differentiation or population of undifferentiated blood, vascular, or cardiac cells, or osteogenic processes.

5. The method of claim 4, wherein said Notch receptor is of the NOTCH-1 receptor subtype.

6. The method of claim 4, wherein said Notch receptor is of the NOTCH-2 receptor subtype.

7. The method of claim 4, wherein said Notch receptor is of the NOTCH-3 receptor subtype.

8. The method of claim 4, wherein said Notch receptor is of the NOTCH-4 receptor subtype.

9. The method of claim 1, wherein said compound is an RNA interfering agent, a blocking antibody or a DNA plasmid.

22. The method of claim 2, wherein said compound is a gamma-secretase inhibitor.

23. The method of claim 22, wherein said cardiovascular disease is atherosclerosis.

24. The method of claim 23, wherein said compound is an RNA interfering agent, a blocking antibody or a DNA plasmid.

10-12. -12. (canceled)

13. A method of determining whether a subject has or is likely to develop a cardiovascular disease, comprising:

a) assaying a test biological sample derived from said subject for the amount, function, or activity of a NOTCH component that is present;

b) comparing the results obtained in step a with those from one or more control samples; and

c) concluding that said subject is at increased risk of having or developing said cardiovascular disease if the level of the amount, function, or activity of said NOTCH component is higher or lower in said test biological sample than in said one or more control samples.

14. The method of claim 13, wherein said Notch component is a NOTCH receptor, a NOTCH ligand selected from the group consisting of:

Delta1 (or Delta-like 1/Dll1), Delta3 (Delta-like 3/Dll3), Delta4 (Delta-like 4/Dll4), Jagged1, and Jagged2, a gamma-secretase component, MAML1, or RBP-Jkappa.

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

atherosclerosis;

heart attack;

restenosis after coronary intervention;

failure of vein grafts for coronary bypass surgery or hemodialysis shunts;

vasculitis;

cardiac damage following acute myocardial infarction;

chronic heart failure;

arterial or valvular calcification; and

stroke.

16. The method of claim 13 wherein said biological sample is a sample of blood, plasma, serum, tissue or cells.

25. The method of claim 13, wherein said cardiovascular disease is atherosclerosis.

26. The method of claim 25, wherein said biological sample is a sample of blood, plasma, serum, tissue or cells.

17-19. -19. (canceled)

20. A method of regenerating a cardiovascular tissue by modulating NOTCH signaling and/or altering expression/activity of molecules relating to the NOTCH pathway.

21. The method of claim 20, wherein said cardiovascular tissue is selected from the group consisting of tissue-engineered arteries, veins, heart valves, and myocardium.