Small molecule-mediated restoration of airway surface physiology in human cystic fibrosis lung epithelia

Abstract

Provided herein are complexes comprising amphotericin B (AmB) or derivatives and sterols. Also provided herein are methods of treating cystic fibrosis using AmB or complexes comprising AmB or derivatives and sterols.

We claim: 
     
         1 . A composition, comprising (i) amphotericin B (AmB), or a pharmaceutically acceptable salt or hydrate thereof, and (ii) cholesterol, wherein the molar ratio of AmB to cholesterol is in the range from 1:2.6 to about 1:50. 
     
     
         2 . The composition of  claim 1 , wherein the molar ratio of AmB to cholesterol is in the range from about 1:4 to about 1:12. 
     
     
         3 . The composition of  claim 1 , wherein the molar ratio of AmB to cholesterol is in the range from about 1:5 to about 1:10. 
     
     
         4 . The composition of any one of  claims 1 - 3 , wherein the AmB and the cholesterol are present as a complex. 
     
     
         5 . The composition of any one of  claims 1 - 4 , wherein the composition is formulated for systemic administration. 
     
     
         6 . The composition of  claim 5 , wherein the composition is formulated for intravenous administration. 
     
     
         7 . The composition of any one of  claims 1 - 4 , wherein the composition is formulated for airway administration. 
     
     
         8 . The composition of  claim 7 , wherein the composition is formulated for aerosol administration. 
     
     
         9 . A composition, comprising (i) C3-deoxy amphotericin B (C3deOAmB), or a pharmaceutically acceptable salt or hydrate thereof, and (ii) cholesterol, wherein the molar ratio of C3deOAmB to cholesterol is in the range from 1:2.6 to about 1:50. 
     
     
         10 . The composition of  claim 9 , wherein the molar ratio of C3deOAmB to cholesterol is in the range from about 1:4 to about 1:12. 
     
     
         11 . The composition of  claim 9 , wherein the molar ratio of C3deOAmB to cholesterol is in the range from about 1:5 to about 1:10. 
     
     
         12 . The composition of any one of  claims 9 - 11 , wherein the C3deOAmB and the cholesterol are present as a complex. 
     
     
         13 . The composition of any one of  claims 9 - 12 , wherein the composition is formulated for systemic administration. 
     
     
         14 . The composition of  claim 13 , wherein the composition is formulated for intravenous administration. 
     
     
         15 . The composition of any one of  claims 9 - 12 , wherein the composition is formulated for airway administration. 
     
     
         16 . The composition of  claim 15 , wherein the composition is formulated for aerosol administration. 
     
     
         17 . A method of treating cystic fibrosis, comprising administering to a subject in need thereof a therapeutically effective amount of a composition comprising (i) amphotericin B (AmB), or a pharmaceutically acceptable salt or hydrate thereof, and (ii) cholesterol, thereby treating the cystic fibrosis. 
     
     
         18 . The method of  claim 17 , wherein the AmB and the cholesterol are present in a molar ratio in the range from about 1:3 to about 1:15. 
     
     
         19 . The method of  claim 17 , wherein the AmB and the cholesterol are present in a molar ratio in the range from about 1:4 to about 1:12. 
     
     
         20 . The method of  claim 18 , wherein the AmB and the cholesterol are present in a molar ratio in the range from about 1:5 to about 1:10. 
     
     
         21 . The method of any one of  claims 17 - 20 , wherein the AmB and the cholesterol are present as a complex. 
     
     
         22 . The method of any one of  claims 17 - 21 , wherein the composition is administered systemically. 
     
     
         23 . The method of  claim 22 , wherein the composition is administered intravenously. 
     
     
         24 . The method of any one of  claims 17 - 21 , wherein the composition is administered to an airway of the subject. 
     
     
         25 . The method of  claim 24 , wherein the composition is administered as an aerosol. 
     
     
         26 . A method of treating cystic fibrosis, comprising administering to a subject in need thereof a therapeutically effective amount of a composition comprising (i) C3-deoxy amphotericin B (C3deOAmB), or a pharmaceutically acceptable salt or hydrate thereof, and (ii) cholesterol, thereby treating the cystic fibrosis. 
     
     
         27 . The method of  claim 26 , wherein the C3deOAmB and the cholesterol are present in a molar ratio in the range from about 1:3 to about 1:15. 
     
     
         28 . The method of  claim 26 , wherein the C3deOAmB and the cholesterol are present in a molar ratio in the range from about 1:4 to about 1:12. 
     
     
         29 . The method of  claim 26 , wherein the C3deOAmB and the cholesterol are present in a molar ratio in the range from about 1:5 to about 1:10. 
     
     
         30 . The method of any one of  claims 26 - 29 , wherein the C3deOAmB and the cholesterol are present as a complex. 
     
     
         31 . The method of any one of  claims 26 - 30 , wherein the composition is administered systemically. 
     
     
         32 . The method of  claim 31 , wherein the composition is administered intravenously. 
     
     
         33 . The method of any one of  claims 26 - 30 , wherein the composition is administered to an airway of the subject. 
     
     
         34 . The method of  claim 33 , wherein the composition is administered as an aerosol. 
     
     
         35 . A method of increasing the pH of airway surface liquid in a subject having cystic fibrosis, comprising administering to a subject having cystic fibrosis a therapeutically effective amount of a composition comprising (i) amphotericin B (AmB), or a pharmaceutically acceptable salt or hydrate thereof, and (ii) cholesterol, thereby increasing the pH of airway surface liquid in the subject having cystic fibrosis. 
     
     
         36 . The method of  claim 35 , wherein the AmB and the cholesterol are present in a molar ratio in the range from about 1:3 to about 1:15. 
     
     
         37 . The method of  claim 35 , wherein the AmB and the cholesterol are present in a molar ratio in the range from about 1:4 to about 1:12. 
     
     
         38 . The method of  claim 35 , wherein the AmB and the cholesterol are present in a molar ratio in the range from about 1:5 to about 1:10. 
     
     
         39 . The method of any one of  claims 35 - 38 , wherein the AmB and the cholesterol are present as a complex. 
     
     
         40 . The method of any one of  claims 35 - 39 , wherein the composition is administered systemically. 
     
     
         41 . The method of  claim 40 , wherein the composition is administered intravenously. 
     
     
         42 . The method of any one of  claims 35 - 39 , wherein the composition is administered to an airway of the subject. 
     
     
         43 . The method of  claim 42 , wherein the composition is administered as an aerosol. 
     
     
         44 . A method of increasing the pH of airway surface liquid in a subject having cystic fibrosis, comprising administering to a subject having cystic fibrosis a therapeutically effective amount of a composition comprising (i) C3-deoxy amphotericin B (C3deOAmB), or a pharmaceutically acceptable salt or hydrate thereof, and (ii) cholesterol, thereby increasing the pH of airway surface liquid in the subject having cystic fibrosis. 
     
     
         45 . The method of  claim 44 , wherein the C3deOAmB and the cholesterol are present in a molar ratio in the range from about 1:3 to about 1:15. 
     
     
         46 . The method of  claim 44 , wherein the C3deOAmB and the cholesterol are present in a molar ratio in the range from about 1:4 to about 1:12. 
     
     
         47 . The method of  claim 44 , wherein the C3deOAmB and the cholesterol are present in a molar ratio in the range from about 1:5 to about 1:10. 
     
     
         48 . The method of any one of  claims 44 - 47 , wherein the C3deOAmB and the cholesterol are present as a complex. 
     
     
         49 . The method of any one of  claims 44 - 48 , wherein the composition is administered systemically. 
     
     
         50 . The method of  claim 49 , wherein the composition is administered intravenously. 
     
     
         51 . The method of any one of  claims 44 - 48 , wherein the composition is administered to an airway of the subject. 
     
     
         52 . The method of  claim 51 , wherein the composition is administered as an aerosol. 
     
     
         53 . The method of any one of  claims 17 - 52 , wherein the subject is a human. 
     
     
         54 . The method of  claim 53 , wherein the human is less than 12 years old. 
     
     
         55 . The method of  claim 53 , wherein the human is at least 12 years old. 
     
     
         56 . A method of treating cystic fibrosis, comprising administering to a subject in need thereof a therapeutically effective amount of a composition comprising amphotericin B (AmB) or a pharmaceutically acceptable salt or hydrate thereof, thereby treating the cystic fibrosis. 
     
     
         57 . A method of increasing the pH of airway surface liquid in a subject having cystic fibrosis, comprising administering to a subject having cystic fibrosis a therapeutically effective amount of a composition comprising amphotericin B (AmB) or a pharmaceutically acceptable salt or hydrate thereof, thereby increasing the pH of airway surface liquid in the subject having cystic fibrosis. 
     
     
         58 . A method of increasing the bicarbonate in airway surface liquid in a subject having cystic fibrosis, comprising administering to a subject having cystic fibrosis a therapeutically effective amount of amphotericin B (AmB), or a pharmaceutically acceptable salt or hydrate thereof, thereby increasing the bicarbonate of airway surface liquid in the subject having cystic fibrosis. 
     
     
         59 . The method of any one of  claims 56 - 58 , wherein the composition is administered systemically. 
     
     
         60 . The method of  claim 59 , wherein the composition is administered intravenously. 
     
     
         61 . The method of any one of  claims 56 - 58 , wherein the composition is administered to an airway of the subject. 
     
     
         62 . The method of  claim 61 , wherein the composition is administered as an aerosol. 
     
     
         63 . The method of any one of  claims 56 - 62 , wherein the subject is a human. 
     
     
         64 . The method of  claim 63 , wherein the human is less than 12 years old. 
     
     
         65 . The method of  claim 63 , wherein the human is at least 12 years old. 
     
     
         66 . The method of any one of  claims 17 - 34  and  56 , wherein the treatment is genotype-independent. 
     
     
         67 . The method of any one of  claims 17 - 66 , wherein the cystic fibrosis is refractory.