Compositions and methods for delivering cftr polypeptides

Abstract

The present disclosure provides recombinant nucleic acids comprising one or more polynucleotides encoding a cystic fibrosis transmembrane conductance regulator (CFTR) polypeptide (e.g., a human CFTR polypeptide); viruses comprising the recombinant nucleic acids; compositions and formulations comprising the recombinant nucleic acids and/or viruses; methods of their use (e.g., for the treatment of a chronic lung disease, such as cystic fibrosis); and articles of manufacture or kits thereof.

What is claimed is: 
     
         1 . A pharmaceutical composition comprising:
 (a) a herpes virus comprising a recombinant herpes virus genome, wherein the recombinant herpes virus genome comprises one or more polynucleotides encoding a cystic fibrosis transmembrane conductance regulator (CFTR) polypeptide; and   (b) a pharmaceutically acceptable excipient.   
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein the herpes virus comprising the recombinant herpes virus genome is replication competent. 
     
     
         3 . The pharmaceutical composition of  claim 1 , wherein the herpes virus comprising the recombinant herpes virus genome is replication defective. 
     
     
         4 . The pharmaceutical composition of  claim 1 , wherein the recombinant herpes virus genome is selected from the group consisting of a recombinant herpes simplex virus genome, a recombinant varicella zoster virus genome, a recombinant human cytomegalovirus genome, a recombinant herpesvirus 6A genome, a recombinant herpesvirus 6B genome, a recombinant herpesvirus 7 genome, a recombinant Kaposi's sarcoma-associated herpesvirus genome, and any derivatives thereof. 
     
     
         5 . The pharmaceutical composition of  claim 4 , wherein the recombinant herpes simplex virus genome is a recombinant herpes simplex virus type 1 (HSV-1) genome. 
     
     
         6 . The pharmaceutical composition of  claim 5 , wherein the recombinant HSV-1 genome has been engineered to reduce or eliminate expression of one or more toxic herpes simplex virus genes. 
     
     
         7 . The pharmaceutical composition of  claim 5 , wherein the recombinant HSV-1 genome comprises an inactivating mutation in a herpes simplex virus gene selected from the group consisting of Infected Cell Protein (ICP) 0, ICP4, ICP22, ICP27, ICP47, thymidine kinase (tk), Long Unique Region (UL) 41, and UL55. 
     
     
         8 . The pharmaceutical composition of  claim 1 , wherein the herpes virus has reduced cytotoxicity as compared to a corresponding wild-type herpes virus. 
     
     
         9 . The pharmaceutical composition of  claim 1 , wherein the CFTR polypeptide comprises a sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 5 or SEQ ID NO: 6. 
     
     
         10 . The pharmaceutical composition of  claim 1 , wherein the pharmaceutical composition is suitable for inhaled administration. 
     
     
         11 . The pharmaceutical composition of  claim 10 , wherein the pharmaceutical composition is suitable for non-invasive inhaled administration. 
     
     
         12 . The pharmaceutical composition of  claim 11 , wherein the pharmaceutical composition is suitable for use in a dry powder inhaler, a pressurized metered dose inhaler, a soft mist inhaler, a nebulizer, an electrohydrodynamic aerosol device, or any combinations thereof. 
     
     
         13 . The pharmaceutical composition of  claim 12 , wherein the nebulizer is a vibrating mesh nebulizer. 
     
     
         14 . A method of providing prophylactic, palliative, or therapeutic relief of one or more signs or symptoms of cystic fibrosis in a subject in need thereof, the method comprising administering to the subject an effective amount of a pharmaceutical composition comprising:
 (a) a herpes virus comprising a recombinant herpes virus genome, wherein the recombinant herpes virus genome comprises one or more polynucleotides encoding a CFTR polypeptide; and   (b) a pharmaceutically acceptable excipient.   
     
     
         15 . The method of  claim 14 , wherein the subject is a human. 
     
     
         16 . The method of  claim 14 , wherein the pharmaceutical composition is administered via inhalation to the subject. 
     
     
         17 . The method of  claim 16 , wherein the pharmaceutical composition is administered via non-invasive inhaled administration. 
     
     
         18 . The method of  claim 17 , wherein the pharmaceutical composition is administered using a dry powder inhaler, a pressurized metered dose inhaler, a soft mist inhaler, a nebulizer, or an electrohydrodynamic aerosol device. 
     
     
         19 . The method of  claim 18 , wherein the nebulizer is a vibrating mesh nebulizer. 
     
     
         20 . The method of  claim 14 , wherein the herpes virus comprising the recombinant herpes virus genome is replication competent. 
     
     
         21 . The method of  claim 14 , wherein the herpes virus comprising the recombinant herpes virus genome is replication defective. 
     
     
         22 . The method of  claim 14 , wherein the recombinant herpes virus genome is selected from the group consisting of a recombinant herpes simplex virus genome, a recombinant varicella zoster virus genome, a recombinant human cytomegalovirus genome, a recombinant herpesvirus 6A genome, a recombinant herpesvirus 6B genome, a recombinant herpesvirus 7 genome, a recombinant Kaposi's sarcoma-associated herpesvirus genome, and any derivatives thereof. 
     
     
         23 . The method of  claim 22 , wherein the recombinant herpes simplex virus genome is a recombinant HSV-1 genome. 
     
     
         24 . The method of  claim 23 , wherein the recombinant HSV-1 genome has been engineered to reduce or eliminate expression of one or more toxic herpes simplex virus genes. 
     
     
         25 . The method of  claim 23 , wherein the recombinant HSV-1 genome comprises an inactivating mutation in a herpes simplex virus gene selected from the group consisting of ICP0, ICP4, ICP22, ICP27, ICP47, tk, UL41, and UL55. 
     
     
         26 . The method of  claim 14 , wherein the herpes virus has reduced cytotoxicity as compared to a corresponding wild-type herpes virus. 
     
     
         27 . The method of  claim 14 , wherein the CFTR polypeptide comprises a sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 5 or SEQ ID NO: 6. 
     
     
         28 . A method of reducing or inhibiting progressive lung destruction in a subject in need thereof, the method comprising administering to the subject an effective amount of a pharmaceutical composition comprising:
 (a) a herpes virus comprising a recombinant herpes virus genome, wherein the recombinant herpes virus genome comprises one or more polynucleotides encoding a CFTR polypeptide; and   (b) a pharmaceutically acceptable excipient.   
     
     
         29 . The method of  claim 28 , wherein the subject suffers from a chronic lung disease. 
     
     
         30 . The method of  claim 29 , wherein the chronic lung disease is cystic fibrosis or chronic obstructive pulmonary disease (COPD).