Compositions and methods for treating progressive myocardial injury due to a vascular insufficiency
View Patent ↗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.
1. A method of treating a progressive myocardial injury that is an adverse consequence of a vascular insufficiency affecting coronary circulation of a subject, comprising
(a) first, acquiring from the subject, under sterile conditions, a population of mononuclear cells comprising CD34+cells;
(b) second, sterilely enriching the population of mononuclear cells for CD34+cells, so that at least 70% of the cells comprising CD34+cells;
(c) third, at least 24 hours after step (a), passing a first portion of the enriched population produced in step (b) through a catheter and confirming that
(i) at least some of the cells passed through said catheter have CXCR-4-mediated chemotactic activity and move in response to SDF-1 in vitro;
(ii) at least some of the cells passed through said catheter can form hematopoietic colonies in vitro; and
(iii) at least 70% of the cells passed through said catheter are viable;
(d) fourth, formulating for parenteral delivery through a catheter a sterile pharmaceutical composition comprising:
(i) a second portion of the enriched population produced in step (b), which contains at least 0.5×10 6 potent CD34+/CXCR-4+cells that have CXCR-4mediated chemotactic activity and that move in response to SDF-1; and
(ii) a stabilizing amount of serum of at least 10% relative to the volume of the sterile pharmaceutical composition, wherein the stabilizing amount is effective to retain the CXCR-4-mediated chemotactic activity and hematopoietic-colony-forming activity of the CD34+/CXCR-4+cells in the second portion of (d)(i);
(e) fifth, administering the sterile pharmaceutical composition to the subject parenterally on a first infusion date; and
(f) sixth, repeating steps (b)-(d), in order, and optionally step (a), at a plurality of infusion dates to treat ongoing vascular insufficiency affecting coronary circulation,
thereby improving myocardial perfusion and preserving existing myocardiocytes and their function during the subject's lifetime.
2. The method according to claim 1 , wherein the acquiring from the subject in (a) is early after occurrence of an acute myocardial infarction.
3. The method according to claim 2 , wherein the acquiring from the subject in (a) is after peak inflammatory cytokine cascade production in an infarcted area.
4. The method according to claim 1 , wherein the acquiring from the subject in a (a) is late after an acute myocardial infarction.
5. The method according to claim 4 , wherein acquiring from the subject in (a) is at least 15 days after an acute myocardial infarction.
6. The method according to claim 1 , wherein the vascular insufficiency is an ischemia.
7. The method according to claim 6 , wherein the ischemia is a myocardial ischemia.
8. The method according to claim 1 , wherein the vascular insufficiency of the coronary vasculature develops after an acute myocardial infarction.
9. The method according to claim 8 , wherein the 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 infarcted area.
10. The method according to claim 9 , wherein the first time of the first infusion date is at least about 5 days post-infarction.
11. The method according to claim 8 , wherein the therapeutic amount is effective to treat cardiomyocyte cell death in the peri-infarct border zone, hypoperfusion in the peri-infarct border zone, myocardial hibernation in the peri-infarct border zone, or a combination thereof, relative to controls.
12. The method according to claim 8 , wherein the therapeutic amount is effective to decrease infarct area, decrease infarct mass, or a combination thereof, relative to controls.
13. The method according to claim 8 , wherein the progressive myocardial injury is a progressive decline in heart muscle function following an acute myocardial infarction.
14. The method according to claim 8 , wherein the at least one adverse consequence of the vascular insufficiency of the coronary vasculature that develops after an acute myocardial infarction is a component of disease progression to heart failure,
wherein the disease progression to heart failure includes recurrent myocardial infarction, development of significant arrhythmias, development of acute coronary syndrome, or a combination thereof.
15. The method according to claim 1 , wherein the progressive myocardial injury is heart failure.
16. The method according to claim 1 , wherein the catheter has an internal diameter of at least about 0.36 mm.
17. The method according to claim 1 , wherein the administering is through the catheter into myocardium, through the catheter intravascularly, or a combination thereof.
18. The method according to claim 1 , wherein the pharmaceutical composition further includes at least one active agent that is compatible both with the CD34+cells, which further contain a subpopulation of potent CD34/CXCR-4cells that have CXCR-4-mediated chemotactic activity and that move in response to SDP-1 and with the stabilizing amount of serum of the composition.
19. The method according to claim 18 , 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.
20. The method according to claim 19 , wherein the tyrosine kinase receptor agonist is human neuregulin 1.
21. The method according to claim 9 , wherein a second infusion date is at least 30 days after occurrence of the acute myocardial infarction.
22. The method according to claim 1 , wherein the mononuclear cells in (a) are cellular components of a bone marrow aspirate.
23. The method according to claim 1 , wherein the mononuclear cells are cellular components of peripheral blood.
24. The method according to claim 9 , wherein a second infusion date is at least 30 days after occurrence of an acute myocardial infarction.
25. The method according to claim 1 , step (a) further comprising apportioning the sterile mononuclear cells into a plurality of aliquots, at least one of which is frozen at 86° C.' and stored in the vapor phase of a liquid nitrogen freezer.
26. The method according to claim 7 , wherein the myocardial ischemia is a transient ischemia or a chronic myocardial ischemia.
27. The method according to claim 7 , wherein the myocardial ischemia is a peri-infarct border zone ischemia.
28. The method according to claim 19 , wherein the cytokine is a hematopoietic stem cell mobilizing agent.
29. The method according to claim 27 , wherein the hematopoietic stem cell mobilizing agent is G-CSF, GM-CSF, or a combination thereof.
30. The method according to claim 19 , wherein the vasoactive agent is an angiotensin converting enzyme inhibitor.
31. The method according to claim 19 , wherein the antiarrhythmic agent is a beta blocker.
32. The method according to claim 1 , wherein the subject is a revascularized subject.
33. The method according to claim 14 , wherein worsening of congestive heart failure, worsening of significant arrhythmias, worsening of acute coronary syndrome, or a combination thereof would lead to premature death in the absence of treatment.