Therapeutic Use of Peptide Inhibitors of NADPH Oxidase; Aerosolization as a Delivery Mechanism

Abstract

A method is provided for treatment of a condition mediated by Nox2 in a patient. The method comprises administering to the patient by inhalation a polypeptide as described herein, able to inhibit superoxide production by Nox2. Conditions treatable in this manner include, without limitation, one or more of: right ventricular hypertrophy; pulmonary hypertension; acute lung injury; obstructive sleep apnea; ischemia/reperfusion injury in the lung; pulmonary fibrosis; an obstructive lung disorder such as Chronic Obstructive Pulmonary Disease (COPD), asthma, cystic fibrosis and emphysema; and atherosclerosis

We claim: 
     
         1 . A method of treating a stroke in a patient, comprising:
 decreasing superoxide anion production by Nox2 in an amount and duration effective to relieve one or more symptoms of the stroke in the patient by administering to the patient a composition comprising a polypeptide consisting of:
 a) a 9-12 amino acid fragment comprising the amino acid sequence 
   
       
         
           
                 
                 
               
                     
                   (SEQ ID NO: 4) 
                 
                     
                   CSTRVRRQL 
                 
             
                
                
               
            
           
         
         
           and 
           b) a tat cell penetration peptide, wherein the tat cell penetration peptide is conjugated to the amino acid fragment, 
           or a pharmaceutically acceptable salt thereof. 
         
       
     
     
         2 . The method of  claim 1 , wherein the polypeptide consists of 
       
         
           
                 
                 
               
                     
                   (SEQ ID NO: 5) 
                 
                     
                   RKKRRQRRRCSTRVRRQL. 
                 
             
                
                
               
            
           
         
       
     
     
         3 . The method of  claim 1 , wherein the symptom of the stroke is ischemia/reperfusion injury. 
     
     
         4 . The method of  claim 1 , wherein the tat cell penetration peptide consists of RKKRRQRRR (SEQ ID NO: 13). 
     
     
         5 . The method of  claim 1 , wherein the fragment a) consists of 
       
         
           
                 
                 
               
                     
                   (SEQ ID NO: 4) 
                 
                     
                   CSTRVRRQL. 
                 
             
                
                
               
            
           
         
       
     
     
         6 . The method of  claim 1 , wherein the composition is administered following the stroke. 
     
     
         7 . A method of treating ischemia/reperfusion injury in a patient, comprising:
 administering to the patient a composition comprising a polypeptide consisting of:
 a) an amino acid fragment consisting of the amino acid sequence 
   
       
         
           
                 
                 
               
                     
                   (SEQ ID NO: 4) 
                 
                     
                   CSTRVRRQL 
                 
             
                
                
               
            
           
         
         
           and 
           b) a cell penetration peptide sequence, wherein the cell penetration peptide sequence is conjugated to the amino acid fragment, 
           or a pharmaceutically-acceptable salt thereof. 
         
       
     
     
         8 . The method of  claim 7 , wherein the polypeptide consists of 
       
         
           
                 
                 
               
                     
                   (SEQ ID NO: 5) 
                 
                     
                   RKKRRQRRRCSTRVRRQL. 
                 
             
                
                
               
            
           
         
       
     
     
         9 . The method of  claim 7 , wherein the cell penetration peptide sequence is selected from the group consisting of tat, oligoarginine, p-antp, plsl, transportan, MPG, and Pep-1. 
     
     
         10 . The method of  claim 7 , wherein the tat cell penetration peptide consists of RKKRRQRRR (SEQ ID NO: 13). 
     
     
         11 . The method of  claim 7 , wherein the ischemia/reperfusion injury is ischemia/reperfusion injury following a stroke. 
     
     
         12 . A composition comprising:
 a polypeptide consisting of:
 a) an amino acid fragment consisting of the amino acid sequence 
   
       
         
           
                 
                 
               
                     
                   (SEQ ID NO: 4) 
                 
                     
                   CSTRVRRQL 
                 
             
                
                
               
            
           
         
         
           and 
           b) a cell penetration peptide sequence, wherein the cell penetration peptide sequence is conjugated to the amino acid fragment, 
         
         or a pharmaceutically-acceptable salt thereof. 
       
     
     
         13 . The composition of  claim 12 , wherein the cell penetration peptide sequence is selected from the group consisting of tat, oligoarginine, p-antp, plsl, transportan, MPG, and Pep-1. 
     
     
         14 . The composition of  claim 12 , wherein the composition further comprises one or more pharmaceutically-acceptable carriers, vehicles, and/or excipients. 
     
     
         15 . The composition of  claim 12 , wherein the polypeptide consists of 
       
         
           
                 
                 
               
                     
                   (SEQ ID NO: 5) 
                 
                     
                   RKKRRQRRRCSTRVRRQL.