Protease resistant mutants of stromal cell derived factor-1 in the repair of tissue damage

Abstract

The present invention is directed stromal cell derived factor-1 peptides that have been mutated to make them resistant to digestion by the proteases dipeptidyl peptidase IV (DPPIV) and matrix metalloproteinase-2 (MMP-2) but which maintain the ability of native SDF-1 to attract T cells. The mutants may be attached to membranes formed by self-assembling peptides and then implanted at sites of tissue damage to help promote repair.

1 . A method of treating a patient to aid the repair of damaged tissue, comprising: administering locally to said damaged tissue, an isolated mutant stromal cell derived factor-1 comprising a peptide having a formula selected from the group consisting of: Xp-SDF-I, mSDF-1 and Xp-mSDF-1, wherein:
 a) X is a proteinogenic amino acid or a protease protective organic group;   b) p is an integer between 1 and 4;   c) SDF-1 is a peptide comprising the amino acid sequence of at least amino acids 1-8 of SEQ ID NO:52 and which is optionally extended at the C terminus by all, or any portion, of the remaining sequence of SEQ ID NO:52, shown as amino acids 9-68;   d) X p -SDF-I has chemoattractant activity for T cells and is inactivated by dipeptidyl peptidase FV (DPPIV) at a rate that is less than one half of the rate at which SDF-I is inactivated;   e) mSDF-1 is a form of SDF-I comprising a mutation in the fourth and/or the fifth amino acid from the N terminus of SDF-I;   f) mSDF-1 has chemoattractant activity for T cells and is inactivated by matrix metalloproteinase-2 (MMP-2) at a rate that is less than one half of the rate at which SDF-I is inactivated; and   g) X p -mSDF-1 has chemoattractant activity for T cells, is inactivated by DPPIV at a rate that is less than one half of the rate at which SDF-I is inactivated and is inactivated by MMP-2 at a rate that is less than one half of the rate at which SDF-I is inactivated.   
     
     
         2 . The method of  claim 1 , wherein said mutant stromal cell derived factor-1 is attached to a biologically compatible membrane or is attached to a self-assembling peptide that forms a biologically compatible membrane after administration locally to said damaged tissue. 
     
     
         3 . The method of  claim 1 , wherein said patient is treated for a disease or condition selected from the group consisting of: stroke; limb ischemia; tissue damage due to trauma; and diabetic ulcers. 
     
     
         4 . The method of  claim 1 , wherein said patient is treated for damage to cardiac tissue and said method comprises injecting or implanting said biologically compatible peptide membrane into the myocardium of said patient.