Polynucleotide compositions, related formulations, and methods of use thereof

A method for enhancing an expression or activity of cystic fibrosis transmembrane conductance regulator (CFTR) protein in a cell, the method comprising:

• contacting said cell with a composition comprising a synthetic polynucleotide assembled with a lipid composition, wherein said synthetic polynucleotide encodes a CFTR protein;
• and wherein said lipid composition comprises:
• an ionizable cationic lipid;
• and
• a selective organ targeting (SORT) lipid separate from said ionizable cationic lipid,
• thereby yielding a therapeutically effective amount or activity of a functional variant of CFTR protein in said cell at least 24 hours after contacting, optionally wherein said therapeutically effective activity of said functional variant of CFTR protein is determined by measuring a change in a transepithelial ion transport characteristic of a plurality of cells comprising said cell as compared to that of a reference plurality of cells in absence of said contacting.

A method for lung secretory cell or lung basal cell delivery, comprising administering to a subject a composition comprising a synthetic polynucleotide assembled with a lipid composition, which synthetic polynucleotide encodes a cystic fibrosis transmembrane conductance regulator (CFTR) protein, wherein said lipid composition comprises:

• an ionizable cationic lipid;
• and
• a selective organ targeting (SORT) lipid separate from said ionizable cationic lipid,
• thereby yielding a therapeutically effective amount or activity of said synthetic polynucleotide in a lung secretory cell of said subject, optionally wherein said therapeutically effective activity of said synthetic polynucleotide is determined by measuring a change in a transepithelial ion transport characteristic of a lung comprising said lung secretory cell or lung basal cell as compared to that of a reference lung in absence of said contacting.

A method for lung secretory cell or lung basal cell delivery, comprising administering to a subject a composition comprising a synthetic polynucleotide assembled with a lipid composition, which synthetic polynucleotide encodes a cystic fibrosis transmembrane conductance regulator (CFTR) protein, wherein said lipid composition comprises:

• an ionizable cationic lipid;
• and
• a selective organ targeting (SORT) lipid separate from said ionizable cationic lipid,
• thereby yielding a greater therapeutic amount or activity of said synthetic polynucleotide in a lung secretory cell or lung basal cell of said subject as compared to that in a lung non-secretory cell or non basal cell of said subject.

A method for lung secretory cell delivery, comprising administering to a subject a composition comprising a synthetic polynucleotide assembled with a lipid composition, which synthetic polynucleotide encodes a cystic fibrosis transmembrane conductance regulator (CFTR) protein, wherein said lipid composition comprises:

• an ionizable cationic lipid;
• and
• a selective organ targeting (SORT) lipid separate from said ionizable cationic lipid,
• thereby yielding a therapeutic amount or activity of said synthetic polynucleotide in at least 5% of lung secretory cells of said subject.