NOTCH inhibition in the treatment of atherosclerosis

• US 8,133,857 B2
• Filed: 03/02/2007
• Issued: 03/13/2012
• 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
• Primary Examiner(s): Bunner, Bridget E
• Application Number:
  US12/230,867
• Publication Number:
  US 20090175849A1
• Time in Patent Office: 1,838 Days
• Field of Search: None
• US Class Current: 514/1
• 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 a patient for atherosclerosis, comprising:

a) assaying a biopsy sample from said patient for the amount or activity of NOTCH-3 receptor or Delta-like 4 (Dll4) and said amount or activity is elevated relative to one or more controls, and wherein said biopsy sample is cells or fluid derived directly from an atherosclerotic plaque; and

b) administering systemically or locally to said patient a therapeutically effective amount of a compound that inhibits the binding of a ligand to the NOTCH-3 receptor, wherein said compound is not an RNA interfering agent or plasmid DNA.

2. The method of claim 1, wherein said compound is administered orally as a capsule, tablet or pill.

3. The method of claim 1, wherein said compound is administered systemically by injection.

4. The method of claim 1, wherein said compound is administered locally by injection.

5. The method of claim 1, wherein said compound is a blocking antibody.

6. The method of claim 1, wherein said ligand is selected from the group consisting of:

Delta-like 4 (Dll4);

Delta-like 3 (Dll3);

Delta-like 1 (Dll1);

Jagged 1; and

Jagged 2.

7. The method of claim 1, wherein said compound also inhibits the binding of a ligand to one or more receptors selected from the group consisting of:

a NOTCH-1 receptor;

a NOTCH-2 receptor; and

a NOTCH-4 receptor.

8. The method of claim 7, wherein said compound is administered orally as a capsule, tablet or pill.

9. The method of claim 7, wherein said compound is administered systemically by injection.

10. The method of claim 7, wherein said compound is administered locally by injection.

11. The method of claim 7, wherein said compound is a blocking antibody.

12. The method of claim 11, wherein said ligand is selected from the group consisting of:

Delta-like 4 (Dll4);

Delta-like 3 (Dll3);

Delta-like 1 (Dll1);

Jagged 1; and

Jagged 2.

13. The method of claim 1, further comprising treating said patient with an additional compound that inhibits the binding of a ligand to one or more receptors selected from the group consisting of:

a NOTCH-1 receptor;

a NOTCH-2 receptor; and

a NOTCH-4 receptor, and wherein said additional compound is not an RNA interfering agent or plasmid DNA.

14. The method of claim 13, wherein said compound and said additional compound are administered orally as a capsule, tablet or pill.

15. The method of claim 13, wherein said compound and said additional compound are administered systemically by injection.

16. The method of claim 13, wherein said compound and said additional compound are administered locally by injection.

17. The method of claim 13, wherein said compound and said additional compound are blocking antibodies.

18. The method of claim 17, wherein said ligand is selected from the group consisting of:

Delta-like 4 (Dll4);

Delta-like 3 (Dll3);

Delta-like 1 (Dll1);

Jagged 1; and

Jagged 2.