Treatment of leaky or damaged tight junctions and enhancing extracellular matrix

Abstract

Self assembling peptides and peptidomimetics can be utilized for the treatment and support of disorders associated with leaky or damaged tight junction and weak, diseased, or injured extracellular matrix. The self-assembling materials generally have alternating hydrophilic or hydrophobic residues or hydrophobic and/or hydrophilic sections which allow the material to react or interact with the glycoproteins found in the ECM. Diseases in which treatment with these materials applied to or near the site in need of treatment include diabetic retinopathy, sepsis, burns, and certain neurodegenerative diseases such as Parkinson's and Alzheimer's. The formulations can be administered by injection, spraying, topically or by catheter or via a wound dressing or other material to which it is applied and then applied to the site in need of treatment.

1 - 47 . (canceled) 
     
     
         48 . A method for treatment of disorders involving leaky or damaged tight junctions and weak, diseased, or injured extracellular matrix comprising
 administering to a subject in need thereof a formulation comprising self-assembling peptides of from 8 to 200 amino acids in length, inclusive,   wherein the self-assembling peptides consist of two or more contiguous motifs of from 4 to 16 amino acid residues conforming to one or more of Formulas I-IV, independently:
   ((Xaa neu -Xaa + ) x (Xaa neu -Xaa − ) y ) n    (I)
 
   ((Xaa neu -Xaa − ) x (Xaa neu -Xaa + ) y ) n    (II)
 
   ((Xaa + -Xaa neu ) x (Xaa − -Xaa neu ) y ) n    (III)
 
   ((Xaa − -Xaa neu ) x (Xaa + -Xaa neu ) y ) n    (IV)
 
   wherein Xaa neu  is an amino acid residue having a neutral charge; Xaa +  is an amino acid residue having a positive charge; Xaa −  is an amino acid residue having a negative charge; x and y are integers having a value of 1, 2, 3 or 4, independently; and n is an integer having a value of 1-5,   with or without one additional amino acid residue at the carboxyl or amino terminus selected from the group consisting of alanine, valine, glycine, isoleucine, phenylalanine, tyrosine, leucine, arginine, lysine, aspartic acid and glutamic acid;   wherein the formulation is administered into a site selected from the group consisting of the blood stream and the interior of a hollow organ, and   wherein the self-assembling peptides undergo a phase transition upon contacting paracellular spaces between cells having leaky or damaged tight junctions and weak, diseased, or injured extracellular matrix, to form a self-assembled barrier structure, and   wherein the self-assembled barrier structure prevents passage of a bodily fluid or contaminant through the leaky or damaged tight junctions and weak, diseased, or injured extracellular matrix.   
     
     
         49 . The method of  claim 48 , wherein Xaa neu  is an amino acid of the formula —NH—CH(X)—COO—, wherein X has the formula (CH 2 ) y Z, wherein y=0-8, Z is a non-polar functional group, wherein (CH 2 ) y  can be in a linear, branched, or cyclic arrangement, and X optionally contains one or more heteroatoms within (CH 2 ) y  or is optionally substituted with one or more additional substituents;
 Xaa +  is an amino acid of the formula —NH—CH(X)—COO—, wherein X has the formula (CH 2 ) y Z, wherein y=0-8 and Z is a polar functional group having a positive charge, wherein (CH 2 ) y  can be in a linear, branched, or cyclic arrangement, and X optionally contains one or more heteroatoms within (CH 2 ) y  or is optionally substituted with one or more additional substituents; and 
 Xaa −  is an amino acid of the formula —NH—CH(X)—COO—, wherein X has the formula (CH 2 ) y Z, wherein y=0-8 and Z is a polar functional group having a negative charge, wherein (CH 2 ) y  can be in a linear, branched, or cyclic arrangement, and X optionally contains one or more heteroatoms within (CH 2 ) y  or is optionally substituted with one or more additional substituents. 
 
     
     
         50 . The method of  claim 49 , wherein Xaa neu  is alanine, valine, glycine, isoleucine, phenylalanine, tyrosine or leucine; Xaa +  is arginine, or lysine; Xaa −  is aspartic acid or glutamic acid. 
     
     
         51 . The method of  claim 48 , wherein the formulation further comprises a pharmaceutically acceptable carrier for administration in the body. 
     
     
         52 . The method of  claim 48 , wherein the formulation is in a form selected from the group consisting of a powder, a solid, a liquid, a gel, nano or microparticles, and a polymeric matrix. 
     
     
         53 . The method of  claim 48 , wherein x and y are 1 and n is 4. 
     
     
         54 . The method of  claim 48 , wherein the self-assembling peptides comprise a sequence of amino acid residues conforming to Formula III or Formula IV. 
     
     
         55 . The method of  claim 48 , wherein the self-assembling peptides are in a solution at a concentration of between 1.0% weight to volume to 4.0% weight to volume, inclusive. 
     
     
         56 . The method of  claim 48 , wherein the self-assembling peptides are in the form of a solid at a concentration of between 1.0% weight to weight to 99.0% weight to weight, inclusive. 
     
     
         57 . The method of  claim 48 , wherein the self-assembling peptides comprise one or more motifs having the sequence RADA. 
     
     
         58 . The method of  claim 57 , wherein one or more motifs is RADARADARADARADA (SEQ ID NO: 60). 
     
     
         59 . The method of  claim 48 , wherein the formulation further comprises an active agent selected from the group consisting of anti-inflammatories, vasoconstrictors, anti-infectives, anesthetics, growth factors, cells, organic compounds, biomolecules, coloring agents, vitamins, and metals. 
     
     
         60 . The method of  claim 48 , wherein the formulation further comprises a therapeutic agent, prophylactic agent, diagnostic agent, a coloring agent, a pharmaceutically acceptable diluent, filler, or oil. 
     
     
         61 . The method of  claim 48 , wherein the formulation is administered to a site selected from the group consisting of a blood vessel, intestines, stomach, heart, biliary tract, gastrointestinal tract, artery, vein, cardiovascular system, and digestive system. 
     
     
         62 . The method of  claim 48 , wherein the subject has impaired coagulation. 
     
     
         63 . The method of  claim 62 , wherein the subject has a coagulation disorder. 
     
     
         64 . The method of  claim 62 , wherein the subject is receiving anticoagulant therapy. 
     
     
         65 . The method of  claim 48 , wherein the subject is need of treatment of sepsis or neurodegeneration. 
     
     
         66 . The method of  claim 48  wherein the formulation is administered in an amount sufficient to provide a reservoir of self-assembling peptides within the body to provide self-assembling material as needed throughout the flowing system. 
     
     
         67 . The method of  claim 48 , wherein the formulation is injected or otherwise introduced into the interior of an organ.