Charge reversal of polyion complexes and treatment of peripheral occlusive disease

• US 20030236214A1
• Filed: 04/15/2003
• Published: 12/25/2003
• Est. Priority Date: 06/09/1999
• Status: Abandoned Application

• Current Assignee: Dr. James E. Hagstrom, Dr. Jon A. Wolff, Julia Hegge, Vladimir G. Budker, Vladimir Trubetskoy
• Original Assignee: Dr. James E. Hagstrom, Dr. Jon A. Wolff, Julia Hegge, Vladimir G. Budker, Vladimir Trubetskoy
• Inventors: Hagstrom, James E., Wolff, Jon A., Hegge, Julia, Budker, Vladimir G., Trubetskoy, Vladimir
• Application Number:
  US10/413,945
• Publication Number:
  US 20030236214A1
• Time in Patent Office: Days
• US Class Current: 514/44.00A
• CPC Class Codes: A61K 38/1825 Fibroblast growth factor [FGF]
• CPC Class Codes: A61K 38/1866 Vascular endothelial growth factor [VEGF]
• CPC Class Codes: A61K 47/645 Polycationic or polyanionic oligopeptides, polypeptides or polyamino acids, e.g. polylysine, polyarginine, polyglutamic acid or peptide TAT
• CPC Class Codes: A61K 48/0041 the non-active part being polymeric

Abstract

A process is described for the delivery of a therapeutic polynucleotide to a tissue suffering from or potentially suffering from ischemia. An ionic polymer is utilized in “recharging” (another layer having a different charge) a condensed polynucleotide complex for purposes of nucleic acid delivery to a cell. The resulting recharged complex can be formed with an appropriate amount of positive or negative charge such that the resulting complex has the desired net charge.

Claims

1. A process delivering a protein or peptide to a muscle tissue of a patient for improving blood flow in the tissue comprising:

a) forming a compound having a net charge comprising a polynucleotide encoding the peptide or protein and a polymer in a solution;

b) adding a charged polymer to the solution in sufficient amount to form a complex having a net charge different from the compound net charge;

c) injecting the complex into a blood vessel lumen, in vivo;

d) increasing permeability in the blood vessel; and

,

e) delivering the complex to an extravascular muscle cell outside of the blood vessel via the increased permeability, wherein the polynucleotide is expressed.

2. The process of claim 1 wherein improving blood flow consists of stimulating new blood vessel formation.

3. The process of claim 1 wherein the peptide or protein consists of an angiogenic factor.

4. The process of claim 3 wherein the angiogenic factor consists of vascular endothelial growth factor.

5. The process of claim 4 wherein the vascular endothelial growth factor is selected from the list consisting of:

VEGF, VEGF II, VEGF-B, VEGF-C, VEGF-D, VEGF-E, VEGF₁₂₁, VEGF₁₃₈, VEGF₁₄₅, VEGF₁₆₅, VEGF₁₈₉ and VEGF₂₀₆.

6. The process of claim 3 wherein the angiogenic factor consists of fibroblast growth factor.

7. The process of claim 6 wherein the fibroblast growth factor is selected from the list consisting of:

FGF-1, FGF-1b, FGF-1c, FGF-2, FGF-2b, FGF-2c, FGF-3, FGF-3b, FGF-3c, FGF-4, FGF-5, FGF-7, FGF-9, acidic FGF and basic FGF.

8. The process of claim 1 wherein the blood vessel consists of a coronary vessel.

9. The process of claim 1 wherein the blood vessel consists of a limb artery.

10. The process of claim 1 wherein the limb artery consists of the femoral artery.

11. The process of claim 1 wherein the permeability of the vessel is increased by inserting papaverine into the vessel prior to or together with the polynucleotides.

12. The process of claim 1, wherein delivery of the polynucleotide stimulates angiogenesis in the muscle tissue.

13. The process of claim 1 wherein enhancing blood flow consists of improving collateral blood flow.

14. The process of claim 13 wherein improving collateral blood flow consists of stimulating collateral blood vessel formation.

15. The process of claim 1 wherein the muscle tissue is affected by a vascular occlusion.

16. The process of claim 1 wherein the muscle tissue is not affected by a vascular occlusion.

17. The process of claim 1 wherein the muscle tissue is suffering from ischemia.

18. The process of claim 1 wherein the muscle tissue is not suffering from ischemia.

19. The process of claim 1 wherein the muscle tissue is heart muscle tissue.

20. The process of claim 19 wherein the heart muscle tissue is human heart muscle tissue.

21. The process of claim 19 wherein delivery of the polynucleotide improves abnormal cardiac function.

22. The process of claim 1 wherein the muscle tissue is skeletal muscle tissue.

23. The process of claim 22 wherein the skeletal muscle tissue is limb skeletal muscle tissue.

24. The process of claim 23 wherein the limb skeletal muscle tissue is human limb skeletal muscle tissue.

25. The process of claim 1 wherein the patient has peripheral vascular disease.

26. The process of claim 1 wherein the patient has peripheral arterial occlusive disease.

27. The process of claim 1 wherein the patient has peripheral-deficient vascular disease.

28. The process of claim 1 wherein the patient has myocardial ischemia.

29. The process of claim 26 wherein the patient suffers from claudication or intermittent claudication.

30. The process of claim 26 wherein delivery of the polynucleotide results in decreased pain associated with a peripheral circulatory disorder.

31. The process of claim 1 wherein the peptide or protein is secreted from the muscle cell.

32. The process of claim 1 wherein the peptide or protein stimulates vascular cell growth.

33. The process of claim 1 wherein delivery of the polynucleotide stimulates vascular cell migration.

34. The process of claim 1 wherein delivery of the polynucleotide stimulates vascular cell proliferation.

35. A process delivering polynucleotides to a muscle tissue for improving blood flow in the tissue comprising:

a) forming a compound having a net charge comprising a polynucleotide and a polymer in a solution;

b) adding a charged polymer to the solution in sufficient amount to form a complex having a net charge different from the compound net charge;

c) injecting the complex into a blood vessel lumen, in vivo; and

,

d) delivering the complex to an extravascular muscle cell outside of the blood vessel via the increased permeability.

36. The process of claim 35 wherein the polynucleotide consists of an RNA function inhibitor.

37. The process of claim 36 wherein the RNA function inhibitor consists of siRNA.

38. The process of claim 37 wherein the siRNA blocks expression of an angiogenesis inhibitor.