Methods for repairing tissue damage using protease-resistant mutants of stromal cell derived factor-1
View Patent ↗The present invention features methods for treating or ameliorating tissue damage using intravenous administration of compositions that include stromal cell derived factor-1 (SDF-1) peptides or mutant SDF-1 peptides that have been mutated to make them resistant to protease digestion, but which retain chemoattractant activity. Systemic delivery, and specifically intravenous (“IV”) delivery, of SDF-1 and protease resistant SDF-1 mutants is very effective for the treatment of tissue damage.
1. A method of treating or ameliorating tissue damage in a subject in need thereof, said tissue damage resulting from a disease or condition selected from the group consisting of stroke, myocardial infarction, chronic heart failure, and diabetic wound healing, wherein said method comprises intravenously administering a composition comprising an isolated mutant form of stromal cell derived factor-1 (SDF-1) peptide comprising the formula of a mutant SDF-1 (mSDF-1), mSDF-1-Y z , X p -mSDF-1, or X p -mSDF-1-Y z , wherein said mSDF-1 is a peptide comprising the amino acid sequence of at least amino acids 1-8 of SEQ ID NO:53 and which is optionally extended at the C-terminus by all or any portion of the remaining sequence of SEQ ID NO:53, said SEQ ID NO:53 comprising the amino acid sequence:
(SEQ ID NO: 53)
K P X 3 X 4 X 5 X 6 Y R C P C R F F E S H V A R A N V K H
L K I L N T P N C A L Q I V A R L K N N N R Q V C I
D P K L K W I Q E Y L E K A L N K,
wherein X 3 , X 4 , X 5 , and X 6 are any amino acid, and wherein
X p is a proteinogenic amino acid(s) or a protease protective organic group and p is any integer from 1 to 4;
Y z is a proteinogenic amino acid(s) or protease protective organic group and z is any integer from 1 to 4;
said mSDF-1 or said mSDF-1-Y z maintains chemoattractant activity for T cells and is inactivated by matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9), leukocyte elastase, and/or cathepsin G at a rate that is at least50% less than the rate of inactivation of native SDF-1; and
said X p -mSDF-1 or said X p -mSDF-1-Y z maintains chemoattractant activity for T cells, is inactivated by dipeptidyl peptidase IV (DPPIV) at a rate that is at least 50% less than the rate at which native SDF-1 is inactivated, and is inactivated by MMP-2, MMP-9, leukocyte elastase, and/or cathepsin G at a rate that is at least 50% less than the rate of inactivation of native SDF-1;
wherein said isolated mutant form of SDF-1 peptide does not comprise the amino acid sequence of at least amino acids 1-8 of SEQ ID NO:52 and is administered intravenously in an amount sufficient to treat or ameliorate said tissue damage in said subject;
and wherein said composition is initially administered:
a) 24 hours or more after onset or diagnosis of said disease, condition, or tissue damage;
b) 48 hours or more after onset or diagnosis of said disease, condition, or tissue damage;
c) 7 days or more after onset or diagnosis of said disease, condition, or tissue damage;
d) one month or more after onset or diagnosis of said disease, condition, or tissue damage; or
e) six months or more after onset or diagnosis of said disease, condition, or tissue damage.
2. The method of claim 1 , wherein said X 3 is valine, histidine, or cysteine.
3. The method of claim 1 , wherein said X 4 is serine or valine.
4. The method of claim 1 , wherein said X 5 is leucine, proline, threonine, or valine.
5. The method of claim 1 , wherein said X 6 is serine, cysteine, or glycine.
6. The method of claim 1 , wherein said peptide is an X p -mSDF-1 peptide or X p -mSDF-1-Y z peptide and wherein X is a serine and p is 1.
7. The method of claim 1 , wherein said peptide is an mSDF-1-Y z peptide or X p -mSDF-1-Y z peptide and wherein Y is a serine and z is 1.
8. The method of claim 1 , wherein said disease or condition is myocardial infarction.
9. The method of claim 1 , wherein said disease or condition is stroke.
10. The method of claim 1 , wherein said disease or condition is chronic heart failure.
11. The method of claim 1 , wherein said disease or condition is diabetic wound healing.
12. The method of claim 1 , wherein said composition is administered to a peripheral or central vein.
13. The method of claim 1 , wherein said method is combined with intra-arterial administration of SDF-1 or a mutant SDF-1 peptide.
14. The method of claim 1 , wherein said disease or condition is tissue damage due to myocardial infarction.
15. The method of claim 1 , wherein said composition is administered one or more times until said tissue damage is reduced, repaired, or new blood vessel formation occurs.
16. The method of claim 1 , wherein said composition is administered one or more times to ameliorate one or more symptoms of said disease or condition.
17. The method of claim 1 , wherein said tissue is a cardiac tissue.
18. The method of claim 1 , wherein said tissue is a vascular tissue.
19. The method of claim 1 , wherein said SDF-1 comprises the sequence of SEQ ID NO: 69.
20. A method of treating or ameliorating tissue damage in a subject in need thereof, said tissue damage resulting from a disease or condition selected from the group consisting of stroke, myocardial infarction, chronic heart failure, and diabetic wound healing, wherein said method comprises intravenously administering a composition comprising an isolated mutant form of stromal cell derived factor-1 (SDF-1) peptide comprising the formula of a mutant SDF-1 (mSDF-1), mSDF-1-Y z , X p -mSDF-1, or X p -mSDF-1-Y z , wherein said mSDF-1 is a peptide comprising the amino acid sequence of at least amino acids 1-8 of SEQ ID NO:53 and which is optionally extended at the C-terminus by all or any portion of the remaining sequence of SEQ ID NO:53. said SEQ ID NO:53 comprising the amino acid sequence:
(SEQ ID NO: 53)
K P X 3 X 4 X 5 X 6 Y R C P C R F F E S H V A R A N V K H
L K I L N T P N C A L Q I V A R L K N N N R Q V C I
D P K L K W I Q E Y L E K A L N K,
wherein X 3 , X 4 , X 5 , and X 6 are any amino acid, and wherein
X p is a proteinogenic amino acid(s) or a protease protective organic group and p is any integer from 1 to 4;
Y z is a proteinogenic amino acid(s) or protease protective organic group and z is any integer from 1 to 4;
said mSDF-1 or said mSDF-1-Y z maintains chemoattractant activity for T cells and is inactivated by matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9), leukocyte elastase, and/or cathepsin G at a rate that is at least 50% less than the rate of inactivation of native SDF-1; and
said X p -mSDF-1 or said X p -mSDF-1-Y z maintains chemoattractant activity for T cells, is inactivated by dipeptidyl peptidase IV (DPPIV) at a rate that is at least 50% less than the rate at which native SDF-1 is inactivated, and is inactivated by MMP-2, MMP-9, leukocyte elastase, and/or cathepsin G at a rate that is at least 50% less than the rate of inactivation of native SDF-1;
wherein said isolated mutant form of SDF-1 peptide does not comprise the amino acid sequence of at least amino acids 1-8 of SEQ ID NO:52 and is administered intravenously in an amount sufficient to treat or ameliorate said tissue damage in said subject.