Compositions and methods for treating progressive myocardial injury due to a vascular insufficiency

• US 9,534,202 B2
• Filed: 10/31/2011
• Issued: 01/03/2017
• Est. Priority Date: 11/07/2005
• Status: Active Grant

• Current Assignee: Caladrius Biosciences, Inc. (Lisata Therapeutics, Inc.)
• Original Assignee: Amorcyte, Inc. (Lisata Therapeutics, Inc.)
• Inventors: Pecora, Andrew L., Preti, Robert A.
• Primary Examiner(s): FOX, ALLISON M
• Application Number:
  US13/285,466
• Publication Number:
  US 20120064045A1
• Time in Patent Office: 1,891 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61P 9/04 Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/06 Antiarrhythmics
• 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: C12N 5/0647 Haematopoietic stem cells; Uncommitted or multipotent progenitors

Abstract

The described invention provides methods and regimens for treating adverse consequences of a persistent and progressive myocardial injury-due to a vascular insufficiency that occurs early or late in a subject in need thereof, and progressive myocardial injury-preventing compositions that contain a chemotactic hematopoietic stem cell product, and, optionally, an additional active agent.

Claims

1. A method for treating progressive decline in heart muscle function due to myocardial ischemia, which comprises

(a) determining eligibility of the subject by clinically evaluating the heart muscle function;

(b) administering parenterally to the subject through a catheter on a first infusion date a sterile pharmaceutical composition comprising a therapeutic amount of a chemotactic hematopoietic stem cell product comprising;

(i) a nonexpanded, isolated population of autologous mononuclear cells enriched for CD34+ cells, which further contains a subpopulation of potent CD34+/CXCR-4+ cells that have CXCR-4-mediated chemotactic activity; and

(ii) a stabilizing amount of serum, wherein the stabilizing amount of serum is at least 10% (v/v) and is effective to retain the CXCR-4-mediated chemotactic activity and hematopoietic colony forming activity of the subpopulation of CD34+/CXCR-4+ cells;

the composition being characterized as having the following properties for at least 24 hours following acquisition of the mononuclear cells when tested in vitro after passage through the catheter;

(1) at least 70% of the cells in the composition are CD34+ cells,

(2) the subpopulation of CD34+/CXCR-4+ cells have CXCR-4-mediated chemotactic activity move in response to SDF-1,

(3) at least 70% of the cells in the composition are viable, and

(4) can form hematopoietic colonies in vitro;

wherein the therapeutic amount of the chemotactic hematopoietic stem cell product comprises at least 10 million isolated CD34+ cells comprising at least 0.5×

10⁶ potent CD34+/CXCR-4+ cells that have CXCR-4-mediated chemotactic activity and that move in response to SDF-1; and

(c) repeating steps (a) through (b) on at least one or more infusion dates during the subject'"'"'s lifetime;

thereby treating the progressive decline in heart muscle function due to myocardial ischemia by;

improving myocardial perfusion of the myocardium and;

reducing apoptosis of existing cardiomyocytes in the myocardium, thereby preserving their function.

2. The method according to claim 1, wherein the myocardial ischemia develops after an acute myocardial infarction.

3. The method according to claim 2, wherein a first infusion date comprises a specific time interval defined by a first time and a second time, and wherein the first time is after peak inflammatory cytokine cascade production in an infarcted area and the second time is before myocardial scar formation in an infarcted area.

4. The method according to claim 3, wherein the first time of the first infusion date is at least about 5 days post-infarction.

5. The method according to claim 3, wherein a second infusion date is at least 30 days after occurrence of an acute myocardial infarction.

6. The method according to claim 3, wherein peak inflammatory cytokine cascade production is determined by measuring a level of at least one inflammatory cytokine in plasma and or urine.

7. The method according to claim 2, wherein the therapeutic amount of the chemotactic hematopoietic stem cell product is effective to treat the myocardium that extends beyond an infarct region of myocardium after the acute myocardial infarction (peri-infarct zone).

8. The method according to claim 7, wherein the therapeutic amount of the chemotactic hematopoietic stem cell product is effective to treat cardiomyocyte cell death in the peri-infarct border zone, hypoperfusion in the pen-infarct border zone, myocardial hibernation in the pen-infarct border zone, or a combination thereof, relative to controls.

9. The method according to claim 2, wherein the therapeutic amount of the chemotactic hematopoietic stem cell product is effective to decrease infarct area, decrease infarct mass, or a combination thereof, relative to controls.

10. The method according to claim 2, wherein the progressive decline in heart muscle function comprises development of congestive heart failure, development of significant arrhythmias, development of an acute coronary syndrome, or a combination thereof.

11. The method according to claim 10, wherein worsening of congestive heart failure, worsening of significant arrhythmias, worsening of acute coronary syndrome, or a combination thereof can lead to premature death without treatment.

12. The method according to claim 10, wherein the development of acute coronary syndrome comprises recurrent myocardial infarction.

13. The method according to claim 2, wherein the progressive decline in heart muscle function comprises a progressive decline in heart muscle function following the acute myocardial infarction.

14. The method according to claim 2, wherein the improvement in myocardial perfusion of the myocardium comprises reducing apoptotic cardiomyocyte cell death and rescuing cardiomyocytes from hibernation in the myocardium.

15. The method according to claim 1, wherein the catheter has an internal diameter of at least about 0.36 mm.

16. The method according to claim 1, wherein the administering is through the catheter into myocardium, through the catheter intravascularly, or a combination thereof.

17. The method according to claim 1, wherein the pharmaceutical composition further includes at least one active agent that is compatible with both components (i) and (ii) of the composition.

18. The method according to claim 17, wherein the active agent is selected from the group consisting of a cytokine, a diuretic, an anti-arrhythmic agent, a tyrosine kinase receptor agonist, an anti-anginal agent, a vasoactive agent, an anticoagulant agent, a fibrinolytic agent, and a hypercholesterolemic agent.

19. The method according to claim 18, wherein the tyrosine kinase receptor agonist is human neuregulin 1.

20. The method according to claim 18, wherein the cytokine is a hematopoietic stem cell mobilizing agent.

21. The method according to claim 20, wherein the hematopoietic stem cell mobilizing agent is G-CSF, GM-CSF, or a combination thereof.

22. The method according to claim 18, wherein the vasoactive agent is an angiotensin converting enzyme inhibitor.

23. The method according to claim 18, wherein the antiarrhythmic agent is a beta blocker.

24. The method according to claim 1, wherein the subject is a revascularized subject.

25. The method according to claim 1, wherein step (a) comprises measuring inflammatory cytokines, cardiac biomarkers, or both.

26. The method according to claim 25, wherein the level of inflammatory cytokines is measured immunochemically.

27. The method according to claim 1, wherein the chemotactic hematopoietic stem cell product of the composition of step (b) is a frozen and thawed chemotactic hematopoietic stem cell product.

28. The method according to claim 1, wherein the myocardial ischemia is a transient ischemia or a chronic myocardial ischemia.

29. The method according to claim 1, wherein the myocardial ischemia is a peri-infarct border zone ischemia.