Compositions and methods for the treatment of cystic fibrosis
Provided herein are polynucleotides, lentiviral vectors, pharmaceutical compositions, and methods of making and using the same, e.g., for treatment of cystic fibrosis (CF).
1 . An isolated polynucleotide comprising a nucleotide sequence of SEQ ID NO: 1 or comprising a nucleotide sequence of SEQ ID NO:3.
2 . A lentiviral transfer vector comprising a) a promoter operably linked to an isolated polynucleotide comprising a nucleotide sequence of SEQ ID NO: 1 or comprising a nucleotide sequence of SEQ ID NO: 3.
3 . The lentiviral transfer vector of claim 2 , wherein the promoter is a human phosphoglycerate kinase promoter (PGK) comprising the nucleotide sequence of SEQ ID NO:4 or an EF1α promoter comprising the nucleotide sequence of SEQ ID NO: 5.
4 . The lentiviral vector of claim 2 , wherein the lentiviral components of the lentiviral vector originate from HIV-1.
5 . The lentiviral vector of claim 2 , further comprising one or more of a 5′ long terminal repeat (LTR), a 3′ LTR, a packaging signal, a Rev response element (RRE), a central polypurine tract (cPPT) sequence, and/or a central termination sequence (CTS).
6 . The lentiviral vector of claim 5 , wherein the 3′ LTR is a self-inactivating 3′LTR.
7 . The lentiviral vector of claim 5 , wherein the 3′ LTR comprises an insertion of a human ankyrin 1 element in the reverse orientation.
8 . A virion comprising the lentiviral vector of claim 2 .
9 . A method of treating cystic fibrosis, the method comprising administering to a subject in need thereof a therapeutically effective amount of the lentiviral vector of claim 2 .
10 . The method of claim 9 , further comprising administering one or more additional therapeutic agents to the subject.
11 . The method of claim 10 , wherein the one or more additional therapeutic agents includes an antibiotic, a mucus thinner, a CFTR modulator, a mucolytic, normal saline, hypertonic saline, or a combination thereof.
12 . The method of claim 9 , wherein the administering is by inhalation, nebulization, atomization or via atomizer, aerosolization, intranasally, intratracheally, intrabronchially, orally, intravenously, subcutaneously, or intramuscularly.
13 . The method of claim 12 , wherein the administering is by inhalation, nebulization, atomization or via atomizer, aerosolization, intranasally, intratracheally, and/or intrabronchially.
14 . An atomizer sprayer or nebulizer comprising the isolated polynucleotide of claim 1 .