Materials and methods for treatment of cystic fibrosis and for induction of ion secretion

Abstract

The present invention provides materials and methods for inducing ion secretion and/or for treating cystic fibrosis. In one embodiment, the composition comprises glucose and/or a non-metabolizable glucose analog and/or non-structural protein (NSP4), a NSP4 peptide, or a NSP4 toxoid as the active ingredient, formulated with pharmaceutically-acceptable carriers. In a preferred embodiment, the composition is in a form of an aerosol preparation for intranasal and/or pulmonary administration, and is used to stimulate chloride and fluid secretion in nasal, tracheal and/or bronchial epithelium.

We claim: 
     
         1 . A pharmaceutical composition comprising a substrate of sodium-glucose transporter (SGLT-1) and a pharmaceutically acceptable carrier, wherein the composition further comprises a NSP4 protein, NSP4 peptide, or NSP4 toxoid. 
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein the SGLT-1 substrate is glucose. 
     
     
         3 . The pharmaceutical composition of  claim 1 , wherein the SGLT-1 substrate is a non-metabolizable glucose analog. 
     
     
         4 . The pharmaceutical composition of  claim 3 , wherein the non-metabolizable glucose analog is selected from the group consisting of α-methyl-D-glucopyranoside (AMG), 3-O-methylglucose (3-OMG), deoxy-D-glucose, and α-methyl-D-glucose. 
     
     
         5 . The pharmaceutical composition of  claim 1 , formulated for intranasal or pulmonary delivery. 
     
     
         6 . The pharmaceutical composition of  claim 1 , formulated as an aerosol. 
     
     
         7 . The pharmaceutical composition of  claim 1 , formulated as a nasal spray. 
     
     
         8 . A pharmaceutical composition consisting essentially of a substrate of sodium-glucose transporter (SGLT-1) as the active ingredient, and optionally, water, pharmaceutically acceptable carriers, excipients, buffering agents, dispersing agents, bulking agents, surfactants, diluents, colorants, and/or preservatives. 
     
     
         9 . The pharmaceutical composition of  claim 1 , further comprising a NSP4 protein, NSP4 peptide, or NSP4 toxoid. 
     
     
         10 . The pharmaceutical composition of  claim 1 , wherein the NSP4 protein, NSP4 peptide, or NSP4 toxoid is present at a concentration of about 0.2 μM to 20 μM. 
     
     
         11 . The pharmaceutical composition of  claim 10 , comprising a NSP4 protein comprising SEQ ID NO:5, a fragment having no less than 8 consecutive amino acids of SEQ ID NO:5, or a peptide having modifications of no more than 5 amino acids of SEQ ID NO:5. 
     
     
         12 . The pharmaceutical composition of  claim 10 , which is formulated so that, during administration, the NSP4 protein, NSP4 peptide, or NSP4 toxoid is not released until the SGLT-1 substrate is released. 
     
     
         13 . The pharmaceutical composition of  claim 1 , wherein the pH is about 7.1 to about 7.5. 
     
     
         14 . The pharmaceutical composition of  claim 1 , wherein the total osmolarity is about 240 mosm to about 390 mosm. 
     
     
         15 . A method for treating cystic fibrosis comprising administering, to a subject in need of such treatment, an effective amount of a composition of  claim 1 . 
     
     
         16 . The method, according to  claim 15 , wherein the composition comprises glucose and/or a non-metabolizable glucose analog. 
     
     
         17 . The method, according to  claim 16 , wherein the composition further comprises a NSP4 protein, NSP4 peptide, or NSP4 toxoid. 
     
     
         18 . The method, according to  claim 17 , wherein the composition further comprises a NSP4 114-135 peptide. 
     
     
         19 . The method of  claim 15 , wherein the composition is administered via intranasal or pulmonary delivery. 
     
     
         20 . A method of inducing ion secretion from cells, comprising administering, to a cell in need of such treatment, an effective amount of a composition of  claim 9 .