Pro-angiogenic peptides and uses thereof

Abstract

This present invention is directed to peptides, compositions, and methods for modulating endogenous cytokine expression in a subject. More specifically, the invention provides peptides useful in regulating the release of a specific pattern of cytokines that promote angiogenesis and/or can be used to modulate the immune system of a subject.

What is claimed is: 
     
       1. A therapeutic peptide consisting of between 5 to 6 amino acids and having a peptide sequence selected from the group consisting of:
 X1-Q-X2-X3-X4-X5; and 
 X1-N-S-X3-X4-X5 
 wherein X1 is selected from the group consisting of N, V, W, and Y; 
 X2 is selected from the group consisting of H, A, and P; 
 X3 is selected from the group consisting of T, Q, and S; 
 X4 is selected from the group consisting of P, Q, H, L, and Y; and 
 X5 is selected from the group consisting of R and S, or is absent. 
 
     
     
       2. The therapeutic peptide of  claim 1 , in a substantially pure form of at least 80% by weight. 
     
     
       3. The therapeutic peptide of  claim 1 , wherein the N-terminus is acetylated and the peptide is pro-angiogenic. 
     
     
       4. A therapeutic composition comprising the therapeutic peptide of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
       5. A method of modulating a cytokine expression in a subject, the method comprising administering to a subject one or more therapeutic peptides of  claim 1 , wherein the therapeutic peptide is administered in an amount sufficient to modulate the expression of at least one endogenous cytokine. 
     
     
       6. The method of  claim 5 , wherein the at least one cytokine is selected from the group consisting of: Eotaxin, Eotaxin-2, ICAM-1, 1-309, IL-4, IL-8, IL-10, IL-11, IL-15, IL-16, IL-17, IL-21, RANTES, sTNF RI, sTNF RII, IL-12p40, IL-12p70, M-CSF, MCP-2, MIG, PDGF-BB, TNF-β, MIP-1b, GCSF, and TIMP-2. 
     
     
       7. The method of  claim 5 , wherein the therapeutic peptide increases the endogenous expression of at least one cytokine selected from the group consisting of: IL-11, IL-12p40, IL-12p70, RANTES, sTNF RI, PDGF-BB, Eotaxin, Eotaxin-2, IL-15, IL-16, IL-17, MCP-2, M-CSF, MIG, TNF-β, sTNF RII, and TIMP-2; and/or decreases the endogenous expression of at least one cytokine selected from the group consisting of: IL-7, IL-8, IL-10, Eotaxin-2, GCSF, ICAM-1, INF-γ, IL-6sR, TIMP-2, MCP-1, and MIP-1b. 
     
     
       8. A method of stimulating wound healing in a subject via induction of angiogenesis, the method comprising: administering the composition of  claim 4  to the subject in an amount sufficient to stimulate angiogenesis of a wound area. 
     
     
       9. The method of  claim 8 , wherein the method comprises modulating the release of a profile of cytokines in the subject, comprising increasing the release in the subject of at least one therapeutically beneficial cytokine and/or inhibiting in the subject the production or release of at least one therapeutically deleterious cytokine. 
     
     
       10. The method of  claim 9 , further comprising stimulating the activity of phagocytic cells and modulating the immune system of that subject to further promote wound healing and decrease inflammation of a wound area. 
     
     
       11. The method of  claim 9 , wherein the cytokine profile released is indicative of a reduction of inflammation. 
     
     
       12. The method of  claim 9 , wherein the at least one beneficial cytokine is PDGF-BB and the at least one deleterious cytokine is IL-8. 
     
     
       13. The method of  claim 9 , wherein the administration of the composition enhances the ability of the immune system to ward off or attenuate infection at the wound. 
     
     
       14. The method of  claim 9 , wherein the amount is within the range of 1 pmole to 1 nmole per g of body weight of the subject. 
     
     
       15. The method of  claim 9 , wherein the amount administered is within the range of 0.1 to 300 mg per dose, and the dose is administered one or two times per week. 
     
     
       16. The method of  claim 9 , wherein the composition is in a formulation suitable for oral administration to the subject, the dosage designed to pass through the subject's stomach before releasing the peptide in the subject's intestine for absorption through the intestinal epithelium. 
     
     
       17. The method of  claim 9 , wherein the composition is administered via a patch comprising: polyethyleneglycol, propylene glycol, methyl paraben, ethyl paraben, hydroxypropylmethyl cellulose, DMSO, isopropyl myristate, mineral oil, white petrolatum, bees wax, or glycerine.