Treatment of vasculopathy with prostacyclin and mesenchymal stem cells

• US 10,080,730 B2
• Filed: 01/08/2014
• Issued: 09/25/2018
• Est. Priority Date: 01/09/2013
• Status: Active Grant

• Current Assignee: United Therapeutics Corporation
• Original Assignee: United Therapeutics Corporation
• Inventors: Jeffs, Roger, Petersen, Thomas, Ilagan, Roger M., Wade, Michael
• Primary Examiner(s): Lankford, Jr., Leon B
• Application Number:
  US14/149,929
• Publication Number:
  US 20140193379A1
• Time in Patent Office: 1,721 Days
• Field of Search: None
• CPC Class Codes: A61K 31/192 having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid cannabinoids A61K31/658
• CPC Class Codes: A61K 31/557 Eicosanoids, e.g. leukotrienes or prostaglandins
• CPC Class Codes: A61K 35/28 Bone marrow; Haematopoietic stem cells; Mesenchymal stem cells of any origin, e.g. adipose-derived stem cells
• 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 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: C12N 2501/00 Active agents used in cell culture processes, e.g. differentation
• CPC Class Codes: C12N 2501/02 Compounds of the arachidonic acid pathway, e.g. prostaglandins, leukotrienes
• CPC Class Codes: C12N 5/0663 Bone marrow mesenchymal stem cells (BM-MSC)

Abstract

Provided are methods for treating or preventing vasculopathy in a subject in need thereof, comprising administering to the subject a prostacyclin and a mesenchymal stem cell (MSC) or a MSC-conditioned culture medium or administering to the subject a MSC or a MSC-conditioned culture medium that has treated with prostacyclin. Pharmaceutical compositions suitable for such treatments are also provided.

Claims

1. A pharmaceutical composition comprising a pharmaceutically effective amount of a mesenchymal stem cell culture and a pharmaceutically acceptable carrier, wherein the mesenchymal stem cell culture comprises treprostinil or a pharmaceutically acceptable salt or ester thereof and is prepared by a method comprising culturing a mesenchymal stem cell in a culture medium and adding an amount of treprostinil or a pharmaceutically acceptable salt or ester thereof to the culture medium during culturing of the mesenchymal stem cell sufficient to increase the amount of vascular endothelial growth factor contained in the mesenchymal stem cell culture.

2. The pharmaceutical composition of claim 1, wherein the mesenchymal stem cell is obtained from bone marrow.

3. The pharmaceutical composition of claim 1, wherein the amount of the treprostinil or pharmaceutically acceptable salt or ester thereof added to the culture medium is between about 200 μ

g/mL and about 300 μ

g/mL.

4. The pharmaceutical composition of claim 1, wherein the mesenchymal stem cell culture comprises vascular endothelial growth factor in an amount two-fold greater than a mesenchymal stem cell culture to which a prostacyclin was not added during culturing.

5. The pharmaceutical composition of claim 1, wherein the mesenchymal stem cell is a mesenchymal precursor cell.

6. A method of preparing a pharmaceutical composition, comprising:

(a) culturing mesenchymal stem cells to form a mesenchymal stem cell culture; and

(b) adding to the mesenchymal stem cell culture an amount of treprostinil or a pharmaceutically acceptable salt or ester thereof sufficient to increase the amount of vascular endothelial growth factor contained in the mesenchymal stem cell culture.

7. The method of claim 6, wherein the mesenchymal stem cells are obtained from bone marrow.

8. The method of claim 6, wherein the amount of the treprostinil or pharmaceutically acceptable salt or ester thereof is between about 200 μ

g/mL and about 300 μ

g/mL.

9. The method of claim 6, wherein the treprostinil or pharmaceutically acceptable salt or ester thereof is present in an amount sufficient to increase the vascular endothelial growth factor in an amount two-fold greater than a mesenchymal stem cell culture without prostacyclin.

10. The method of claim 6, wherein the mesenchymal stem cells are mesenchymal precursor cells.

11. The method of claim 6, further comprising isolating exosomes from the mesenchymal stem cell culture.