Nuclear localization of GLP-1 stimulates myocardial regeneration and reverses heart failure

• US 10,028,902 B2
• Filed: 11/07/2014
• Issued: 07/24/2018
• Est. Priority Date: 11/08/2013
• Status: Active Grant

• Current Assignee: Baylor Research Institute (Baylor University)
• Original Assignee: Baylor Research Institute (Baylor University)
• Inventors: Grayburn, Paul A., Chen, Shuyuan
• Primary Examiner(s): Kelly, Robert M
• Application Number:
  US15/034,929
• Publication Number:
  US 20160263017A1
• Time in Patent Office: 1,355 Days
• Field of Search: None
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/616 by carboxylic acids, e.g. acetylsalicylic acid
• CPC Class Codes: A61K 31/7048 having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin , digitoxin or digoxin
• CPC Class Codes: A61K 38/2292 Thymosin; Related peptides
• CPC Class Codes: A61K 38/26 Glucagons
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 48/0016 wherein the nucleic acid is delivered as a 'naked' nucleic acid, i.e. not combined with an entity such as a cationic lipid
• CPC Class Codes: A61K 48/0075 characterised by an aspect of the delivery route, e.g. oral, subcutaneous
• CPC Class Codes: A61K 9/0009 involving or responsive to electricity, magnetism or acoustic waves; Galenical aspects of sonophoresis, iontophoresis, electroporation or electroosmosis microelectromechanical systems A61K9/0097
• CPC Class Codes: A61K 9/127 Liposomes
• CPC Class Codes: C12N 15/87 Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation

Abstract

Embodiments of the disclosure provide methods and/or compositions useful for an individual in need of treatment of a cardiac-related medical condition. In particular cases, GLP-1 is employed in a ultrasound targeted microbubble destruction (UTMD) system for delivery to cardiac tissue, thereby stimulating myocardial regeneration and, in at least some cases, reversal of cardiomyopathy.

Claims

1. A method of localizing glucagon-like peptide (GLP)-1 to the nucleus of cells that are cardiomyocytes, skeletal myocytes, or smooth muscle myocytes, comprising the steps of:

providing to the cells an effective amount of lipid-stabilized microbubbles having liposomes attached to the outer surface of a shell of the microbubbles, incorporated within the shell of the microbubbles, and/or encapsulated within the shell of the microbubbles, wherein the liposomes comprise GLP-1 or a nucleic acid that encodes GLP-1 encapsulated within or attached to the liposome; and

exposing the microbubbles to ultrasound conditions sufficient to deliver GLP-1 or the nucleic acid that encodes GLP-1 into the nuclei of the cells, wherein the microbubbles further comprise thymosin beta 4 (TB4).

2. The method of claim 1, wherein the cell membrane of the cells lacks GLP-1 receptors.

3. The method of claim 1, wherein the cell membrane of the cells has GLP-1 receptors.

4. The method of claim 1, wherein the cells are located in vitro.

5. The method of claim 1, wherein the cells are located in vivo.

6. The method of claim 1, wherein the nucleic acid that encodes GLP-1 is delivered into the nuclei of the cells.

7. The method of claim 1, wherein GLP-1 is delivered into the nuclei of the cells.

8. The method of claim 6, wherein the nucleic acid is comprised in a vector.

9. The method of claim 6, wherein the nucleic acid further comprises sequence that encodes a nuclear localization signal.

10. The method of claim 1, wherein the microbubbles further comprise albumin, polymer shell, or a graphite shell.

11. The method of claim 1, wherein the microbubbles further comprise a gas.

12. The method of claim 5, wherein the cells are in an individual that has a cardiac-related medical condition.

13. The method of claim 12, wherein the cardiac-related medical condition is a cardiomyopathy that is induced by a drug.

14. The method of claim 13, wherein the drug is a chemotherapy drug.

15. The method of claim 13, wherein the drug is Adriamycin.

16. A method of localizing glucagon-like peptide (GLP)-1 to the nucleus of cells that are cardiomyocytes, skeletal myocytes, or smooth muscle myocytes, comprising the steps of:

providing to the cells an effective amount of lipid-stabilized microbubbles having liposomes attached to the outer surface of a shell of the microbubbles, incorporated within the shell of the microbubbles, and/or encapsulated within the shell of the microbubbles, wherein the liposomes comprise GLP-1 or a nucleic acid that encodes GLP-1 encapsulated within or attached to the liposome; and

exposing the microbubbles to ultrasound conditions sufficient to deliver GLP-1 or the nucleic acid that encodes GLP-1 into the nuclei of the cells, wherein the cells are in an individual that has a cardiomyopathy that is induced by a drug.

17. The method of claim 16, wherein the drug is Adriamycin.

18. The method of claim 16, wherein the cell membrane of the cells lacks GLP-1 receptors.

19. The method of claim 16, wherein the cell membrane of the cells has GLP-1 receptors.

20. The method of claim 16, wherein the cells are located in vitro.

21. The method of claim 16, wherein the cells are located in vivo.

22. The method of claim 16, wherein nucleic acid that encodes GLP-1 is delivered into the nuclei of the cells.

23. The method of claim 16, wherein GLP-1 is delivered into the nuclei of the cells.

24. The method of claim 22, wherein the nucleic acid is comprised in a vector.

25. The method of claim 22, wherein the GLP-1 nucleic acid further comprises sequence that encodes a nuclear localization signal.

26. The method of claim 16, wherein the microbubbles further comprise albumin, polymer shell, or a graphite shell.

27. The method of claim 16, wherein the microbubbles further comprise a gas.