Saposin-A derived peptides and uses thereof
The invention relates to isolated peptides and chimeric polypeptides derived from Saposin A that have anti-angiogenic activity. These peptides are small, consisting essentially of at least 10 consecutive amino acid residues from the 31st-50 th amino acid residue of Saposin A. The invention also relates to the use of these isolated peptides and chimeric polypeptides in compositions for the treatment, prevention, and inhibition of angiogenesis-related diseases and disorders such as cancer and cancer metastasis.
1. An isolated peptide consisting of the amino acid sequence CDWLPKPNMSASC (SEQ ID NO: 37), wherein the peptide is:
(a) cyclic;
(b) N-terminal acetylated or thioglycolic acid amidated;
(c) C-terminal carboxylamidated;
(d) pegylated; or
(e) conjugated to a polymer that enhances the serum half-life of the peptide.
2. An isolated chimeric polypeptide comprising a first portion and a second portion, wherein said first portion is the peptide of claim 1 , and wherein said second portion is not a Psap peptide.
3. A composition comprising the peptide of claim 1 , and a pharmaceutically acceptable carrier.
4. A method for treatment of an angiogenesis-dependent disease or disorder, comprising: administering to a subject in need thereof a therapeutically effective amount of the peptide of claim 1 .
5. A method of inhibiting the recurrence of an angiogenesis-dependent disease or disorder, the method comprising administering to a subject in need thereof a therapeutically effective amount of the peptide of claim 1 .
6. A method of inhibiting metastasis of cancer in a subject diagnosed with cancer, the method comprising administering to the subject a therapeutically effective amount of the peptide of claim 1 .
7. The method of claim 4 , wherein the angiogenesis-dependent disease or disorder is selected from a group consisting of cancer, psoriasis, age-related macular degeneration, thyroid hyperplasia, preeclampsia, rheumatoid arthritis and osteoarthritis, Alzheimer's disease, obesity, pleural effusion, atherosclerosis, endometriosis, diabetic/other retinopathies, neovascular glaucoma, age-related macular degeneration, hemangiomas, and corneal neovascularization.
8. The method of claim 4 , wherein the peptide is administered in conjunction with chemotherapy, radiation therapy, a cytostatic agent, an anti-VEGF agent, an anti-angiogenesis factor, and/or a p53 reactivation agent.
9. A method of treating an angiogenesis-dependent disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of the composition of claim 3 .
10. A method of inhibiting the recurrence of an angiogenesis-dependent disease or disorder, the method comprising administering to a subject in need thereof a therapeutically effective amount of the composition of claim 3 .
11. A method of inhibiting metastasis of cancer in a subject diagnosed with cancer, the method comprising administering to the subject a therapeutically effective amount of the composition of claim 3 .
12. A method of treating an individual diagnosed with cancer comprising:
a) determining a level of Psap in a tumor sample from said individual;
b) comparing the Psap level determined in a) with a reference Psap level; and
c) wherein said Psap level determined in a) is lower than 95% of said reference Psap level,
administering a therapeutically effective amount of a composition of claim 3 .
13. The method of claim 9 , wherein the angiogenesis-dependent disease or disorder is selected from a group consisting of cancer, psoriasis, age-related macular degeneration, thyroid hyperplasia, preeclampsia, rheumatoid arthritis and osteoarthritis, Alzheimer's disease, obesity, pleural effusion, atherosclerosis, endometriosis, diabetic/other retinopathies, neovascular glaucoma, age-related macular degeneration, hemangiomas, and corneal neovascularization.
14. The method of claim 9 , wherein the composition is administered in conjunction with chemotherapy, radiation therapy, a cytostatic, an anti-VEGF agent, an antiangiogenesis factor, and/or a p53 reactivation agent.
15. The isolated peptide of claim 1 , wherein the peptide is capable of activating p53 and inducing Tsp-1 expression.
16. The isolated peptide of claim 1 , wherein the peptide is fused/conjugated to a therapeutic molecule.
17. The isolated peptide of claim 1 , wherein the cyclization comprises cyclization of the amino and the carboxyl termini of the peptide by a disulfide bond or a covalent bond.
18. The isolated peptide of claim 1 , wherein the linker is (Gly 4 Ser) 3 (SEQ ID NO: 82).
19. The isolated peptide of claim 17 , wherein the covalent bond is a peptide bond.