Methods for Increasing the Selective Efficacy of Gene Therapy Using CAR Peptide and Heparan-Sulfate Mediated Macropinocytosis

Abstract

Disclosed are compositions and methods for triggering disease selective macropinocytosis. The compositions can serve as a marker of disease activity and as a trigger of enhanced macropinocytosis in tissues undergoing disease remodeling such as wound healing, cancer, PAH, inflammation, diabetes, Crohn's disease, ulcerative colitis, ankylosing spondylitis, diseases of the endometrium, psoriasis, irritable bowel syndrome, arthritis, fibrotic disorders, interstitial cystitis, autoimmune diseases, asthma, acute lung injury, and adult respiratory distress syndrome. The compositions can also serve as a receptor for disease selective cell penetrating peptides in the cells and extracellular matrix of diseased tissues.

I claim: 
     
         1 . A method for diagnosing the health status of an individual suffering from Pulmonary Arterial Hypertension (PAH), the method comprising:
 a) obtaining a sample from an individual suffering from PAH;   b) measuring heparanase and heparan sulfate levels in the sample obtained in step a);   c) determining the health status of the individual based on the heparanase and heparan sulfate levels obtained in step b.   
     
     
         2 . The method of  claim 1 , wherein the sample is selected from the group consisting of tissue, blood and urine. 
     
     
         3 . The method of  claim 2 , wherein the sample is a blood sample. 
     
     
         4 . The method of  claim 2 , wherein the same is a urine sample. 
     
     
         5 . A method for increasing the localized efficacy of gene therapy in an individual suffering from a disease by co-administering a therapeutically effective amount of a composition consisting of:
 1) at least one cell-penetrating peptide; and   2) at least one other therapeutic agent,   
       wherein at least one compound of the composition induces increased macropinocytosis of diseased cells. 
     
     
         6 . The method of  claim 5 , wherein the disease is further characterized by tissue with increased heparanase expression. 
     
     
         7 . The method of  claim 6 , wherein the disease is selected from the group consisting of pulmonary hypertension (PAH), interstitial lung disease, acute lung injury (ALI), acute respiratory distress syndrome (ARDS), atherosclerosis, sepsis, septic shock, sarcoidosis of the lung, diabetes, asthma, ankylosing spondylitis, psoriasis, diseases of the endometrium, pulmonary manifestations of connective tissue diseases, including systemic lupus erythematosus, rheumatoid arthritis, scleroderma, and polymyositis, dermatomyositis, bronchiectasis, asbestosis, berylliosis, silicosis, Histiocytosis X, pneumotitis, smoker's lung, bronchiolitis obliterans, the prevention of lung scarring due to tuberculosis and pulmonary fibrosis, other fibrotic diseases such as myocardial infarction, endomyocardial fibrosis, mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis, progressive massive fibrosis, pneumoconiosis, nephrogenic systemic fibrosis, keloid, arthrofibrosis, adhesive capsulitis, radiation fibrosis, fibrocystic breast condition, liver cirrhosis, hepatitis, liver fibrosis, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, sarcoidosis of the lymph nodes, or other organs, inflammatory bowel disease, Crohn's disease, ulcerative colitis, primary biliary cirrhosis, pancreatitis, interstitial cystitis, chronic obstructive pulmonary disease, pneumoconiosis, autoimmune diseases, cancer, angiogenic diseases, wound healing, erectile dysfunction, chronic kidney disease, infections, trauma injuries and systemic connective tissue diseases including systemic lupus erythematosus, rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis scleroderma, polymyositis, and dermatomyositis. 
     
     
         8 . The method of  claim 7 , wherein the disease is PAH. 
     
     
         9 . The method of  claim 5 , wherein the cell-penetrating peptide is selected from the group consisting of CAR (SEQ ID NO: 1), tCAR (SEQ ID NO: 2) or a CAR variant with at least 60% binding affinity to IdoA2s-GlcNS. 
     
     
         10 . The method of  claim 9 , wherein the cell-penetrating peptide is CAR. 
     
     
         11 . The method of  claim 9 , wherein the cell-penetrating peptide is tCAR. 
     
     
         12 . The method of  claim 9 , wherein the cell-penetrating peptide is a CAR variant with at least 60% binding affinity to IdoA2s-GlcNS. 
     
     
         13 . The method of  claim 9 , wherein the therapeutic agent is selected from the group consisting of small molecules, polypeptides, peptides, peptidomimetics, nucleic acid-molecules, cells and viruses.