Compositions and methods for treating cellular response to injury and other proliferating cell disorders regulated by hyaladherin and hyalurons

Abstract

The present invention provides compositions and methods for treating a tissue disorder associated with a response-to-injury process or proliferating cells in a mammal. These tissue disorders are associated with a novel cellular phenotype designated as “transition cells” which are described herein. This cellular phenotype is characterized in having an activated erk kinase signaling activity, a stimulated AP-1 binding activity, and at least one characteristic selected from the group consisting of: (a) increased podosome formation, (b) increased flux of intracellular or extracellular hyaluronans or hyaladherins, (c) increased expression of a hyaladherin, (d) an inability to form focal adhesions, (e) increased metalloproteinase activity, and (f) increased expression of a hyaladherin. Example tissue disorders include fibrosis, inflammation, degeneration and invasive disorders such as occur in cancerous cells. The methods provided herein include administering to the mammal, an effective amount of a composition that alters the activity of transition molecules within a cell Transition molecules are shown to be comprised of hyaladherins, hyaluronans and associated molecules that regulate the transitional phenotype. A novel cell culture comprising transition cells is also provided, as well as compositions comprising particular peptides, polypeptides, and antibodies that affect the transitional phenotype.

1 . A method for treating a patient with a inflammatory neurological disorder, comprising administering to a patient a compound selected from the group consisting of (a) a polypeptide comprising the amino acid sequence BX7B which binds HA; (b) an antibody which binds one of domains D1, D2, D3, D4, or, D5 of RHAMM; (c) a polypeptide fragment which encodes a D1, D2, D3, D4, or, D5 domain of RHAMM; and (d) a gene delivery vector which expresses antisense RHAMM, or, delivers and expresses any one of (a), (b), or (c), such that said inflammatory neurological disorder is treated.  
     
     
         2 . The method according to  claim 1  wherein said inflammatory neurological disorder is Parkinsons disease.  
     
     
         3 . The method according to  claim 1  wherein said inflammatory neurological disorder is Alzheimer disease  
     
     
         4 . A method for treating a patient with arthritis, comprising administering to a patient a compound selected from the group consisting of (a) a polypeptide comprising the amino acid sequence BX7B which binds HA; (b) an antibody which binds one of domains D1, D2, D3, D4, or, D5 of RHAMM; (c) a polypeptide fragment which encodes a D1, D2, D3, D4, or, D5 domain of RHAMM; and (d) a gene delivery vector which expresses antisense RHAMM, or, delivers and expresses any one of (a), (b), or (c), such that said arthritis is treated.  
     
     
         5 . The method according to  claim 4  wherein said arthritis is rheumatoid arthritis.  
     
     
         6 . The method according to  claim 4  wherein said arthritis is osteoarthritis.  
     
     
         7 . A method for treating a patient with multiple sclerosis, comprising administering to a patient a compound selected from the group consisting of (a) a polypeptide comprising the amino acid sequence BX7B which binds HA; (b) an antibody which binds one of domains D1, D2, D3, D4, or, D5 of RHAMM; (c) a polypeptide fragment which encodes a D1, D2, D3, D4, or, D5 domain of RHAMM; and (d) a gene delivery vector which expresses antisense RHAMM, or, delivers and expresses any one of (a), (b), or (c), such that said multiple sclerosis is treated.  
     
     
         8 . A method for treating a patient with inflammatory dermatosis, comprising administering to a patient a compound selected from the group consisting of (a) a polypeptide comprising the amino acid sequence BX7B which binds HA; (b) an antibody which binds one of domains D1, D2, D3, D4, or, D5 of RHAMM; (c) a polypeptide fragment which encodes a D1, D2, D3, D4, or, D5 domain of RHAMM; and (d) a gene delivery vector which expresses antisense RHAMM, or, delivers and expresses any one of (a), (b), or (c), such that said inflammatory dermatitis is treated.  
     
     
         9 . The method according to  claim 8  wherein said inflammatory dermatosis is psoriasis.  
     
     
         10 . A method for treating a patient with inflammatory, bowel disease, comprising administering to a patient a compound selected from the group consisting of (a) a polypeptide comprising the amino acid sequence BX7B which binds HA; (b) an antibody which binds one of domains D1, D2, D3, D4, or, D5 of RHAMM; (c) a polypeptide fragment which encodes a D1, D2, D3, D4, or, D5 domain of RHAMM, and (d) a gene delivery vector which expresses antisense RHAMM, or, delivers and expresses any one of (a), (b), or (c), such that said inflammatory bowel disease is treated.  
     
     
         11 . A method for treating wounds, comprising administering to a patient a compound selected from the group consisting of (a) a polypeptide comprising the amino acid sequence BX7B which binds HA; (b) an antibody which binds one of domains D1, D2, D3, D4, or, D5 of RHAMM; (c) a polypeptide fragment which encodes a D1, D2, D3, D4, or, D5 domain of RHAMM; and (d) a gene delivery vector which expresses antisense RHAMM, or, delivers and expresses any one of (a), (b), or (c), such that said wound is treated.  
     
     
         12 . The method according to  claim 11  wherein said wound is a surgical excision.  
     
     
         13 . The method according to  claim 11  wherein said method is utilized to prevent a surgical adhesion.  
     
     
         14 . The method according to  claim 11  wherein said method is utilized to prevent a scar.  
     
     
         15 . A method for treating stenosis or restenosis, comprising administering to a patient a compound selected from the group consisting of (a) a polypeptide comprising the amino acid sequence BX7B which binds HA; (b) an antibody which binds one of domains D1, D2 D3, D4, or, D5 of RHAMM; (c) a polypeptide fragment which encodes a D1, D2, D3, D4, or, D5 domain of RHAMM; and (d) a gene delivery vector which expresses antisense RHAMM, or, delivers and expresses any one of (a), (b), or (c), such that said stenosis or restenosis is treated.  
     
     
         16 . The method according to  claim 15 , wherein said compound is administered through a balloon catheter.  
     
     
         17 . The method according to  claim 15  wherein said compound is applied to a stent, which is placed in said patient.  
     
     
         18 . The method according to  claim 15  wherein said compound is administered to the outside to the vessel to be treated.  
     
     
         19 . A method for treating cancer, comprising administering to a patient a compound selected from the group consisting of (a) a polypeptide comprising the amino acid sequence BX7B which binds HA; (b) an antibody which binds one of domains D1, D2, D3, D4, or, D5 of RHAMM; (c) a polypeptide fragment which encodes a D1, D2, D3, D4, or, D5 domain of RHAMM; and (d) a gene delivery vector which expresses antisense RHAMM, or, delivers and expresses any one of (a), (b), or (c), such that said cancer is treated.  
     
     
         20 . A method for treating kidney fibrosis, comprising administering to a patient a compound selected from the group consisting of (a) a polypeptide comprising the amino acid sequence BX7B which binds HA; (b) an antibody which binds one of domains D1, D2, D3, D4, or, D5 of RHAMM; (c) a polypeptide fragment which encodes a D1, D2, D3, D4, or, D5 domain of RHAMM; and (d) a gene delivery vector which expresses antisense RHAMM, or, delivers and expresses any one of (a), (b), or (c), such that said kidney fibrosis is treated.  
     
     
         21 . A method for treating inflammatory lung disease, comprising administering to a patient a compound selected from the group consisting of (a) a polypeptide comprising the amino acid sequence BX7B which binds HA; (b) an antibody which binds one of domains D1, D2, D3, D4, or, D5 of RHAMM; (c) a polypeptide fragment which encodes a D1, D2, D3, D4, or, D5 domain of RHAMM; and (d) a gene delivery vector which expresses antisense RHAMM, or, delivers and expresses any one of (a), (b), or (c), such that said inflammatory lung disease is treated.  
     
     
         22 . The method according to  claim 21  wherein said inflammatory lung disease is emphysema.  
     
     
         23 . The method according to  claim 21  wherein said inflammatory lung disease is asthma.  
     
     
         24 . The method according to  claim 21  wherein said inflammatory lung disease is cystic fibrosis.  
     
     
         25 . A method for treating obesity and obesity related diseases, comprising administering to a patient a compound selected from the group consisting of (a) a polypeptide comprising the amino acid sequence BX7B which binds HA; (b) an antibody which binds one of domains D1, D2, D3, D4, or, D5 of RHAMM; (c) a polypeptide fragment which encodes a D1, D2, D3, D4, or, D5 domain of RHAMM; and (d) a gene delivery vector which expresses antisense RHAMM, or, delivers and expresses any one of (a), (b), or (c), such that said obesity and obesity-related diseases are treated.  
     
     
         26 . A method for treating lupus, comprising administering to a patient a compound selected from the group consisting of (a) a polypeptide comprising the amino acid sequence BX7B which binds HA; (b) an antibody which binds one of domains D1, D2, D3, D4, or, D5 of RHAMM; (c) a polypeptide fragment which encodes a D1, D2, D3, D4, or, D5 domain of RHAMM; and (d) a gene delivery vector which expresses antisense RHAMM, or, delivers and expresses any one of (a), (b), or (c), such that said lupus is treated.  
     
     
         27 . A method for treating cardiovascular disease, comprising administering to a patient a compound selected from the group consisting of (a) a polypeptide comprising the amino acid sequence BX7B which binds HA; (b) an antibody which binds one of domains D1, D2, D3, D4, or, D5 of RHAMM; (c) a polypeptide fragment which encodes a D1, D2, D3, D4, or, D5 domain of RHAMM; and (d) a gene delivery vector which expresses antisense RHAMM, or, delivers and expresses any one of (a), (b), or (c), such that said cardiovascular disease is treated.  
     
     
         28 . The method according to  claim 27  wherein said cardiovascular disease is atherosclerosis.  
     
     
         29 . An antibody which binds to any one of domains D1, D2, D3, D4, or, D5 of RHAMM.  
     
     
         30 . The antibody according to  claim 29  wherein said RHAMM is human RHAMM.  
     
     
         31 . The antibody according to  claim 29  wherein said antibody is a monoclonal antibody.  
     
     
         32 . The antibody according to  claim 31  wherein said monoclonal antibody is a human monoclonal antibody.  
     
     
         33 . The antibody according to  claim 31  wherein said monoclonal antibody is an Fab fragment of an antibody.  
     
     
         34 . A polypeptide fragment comprising all or a portion of domains D1, D2, D3, D4, or, D5 of RHAMM, wherein said polypeptide is less than 73 kD molecular weight.  
     
     
         35 . The polypeptide fragment according to  claim 34 , wherein said polypeptide is less than 100 amino acids in length.  
     
     
         36 . The polypeptide fragment according to  claim 34  wherein said polypeptide fragment is less than 75 amino acids in length.  
     
     
         37 . A method for treating or preventing diabetes mellitus, comprising administering to a patient a compound selected from the group consisting of (a) a polypeptide comprising the amino acid sequence BX7B (SEQ ID NO:28); (b) an antibody which binds one of domains D1, D2, D3, D4, or D5 of RHAMM; (c) a peptide of less than 95 kD or 73 kd, comprising all or a portion of domains D1, D2, D3, D4, or, D5 of RHAMM; and (d) a gene delivery vector which expresses antisense RHAMM, or, delivers and expresses any one of (a), (b), or (c), such that the disease is treated.