Polynucleotide compositions, related formulations, and methods of use thereof
Inventors
Hennig, Mirko • Ishimaru, Daniella • Lockhart, David J. • Torres, Michael • EBY, Jackson • Boudko, Dmitri • Wustman, Brandon A.
Assignees
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Publication Number
US-12257318-B2
Publication Date
2025-03-25
Expiration Date
Abstract
Compositions of polynucleotide(s), pharmaceutical compositions thereof, and methods of use thereof are disclosed. A polynucleotide may encode for a cystic fibrosis transmembrane conductance regulator (CFTR) protein or a functional fragment thereof. The polynucleotide may be assembled with a lipid composition for targeted delivery to a cell or an organ, such as a lung cell or a lung of a subject. Methods for enhancing an expression or activity of CFTR protein in a cell are provided. Methods for treating a subject having or suspected of having a CFTR-associated condition are also provided.
Core Innovation
A pharmaceutical composition comprises a synthetic polynucleotide assembled with a lipid composition. The synthetic polynucleotide encodes a cystic fibrosis transmembrane conductance regulator (CFTR) protein and includes a nucleic acid sequence having at least about 98% sequence identity to SEQ ID NO: 4.
The lipid composition includes an ionizable cationic lipid, a selective organ targeting (SORT) lipid separate from the ionizable cationic lipid, a phospholipid, a steroid or steroid derivative, and a polymer-conjugated lipid. The composition is defined by molar percentage ranges for each lipid component.
The disclosure also includes targeted pulmonary delivery and engineered RNA design features, including 3′/5′ noncoding regions, a 5′ cap structure, a poly(A) tail, codon optimization strategies, nucleotide analogues or modifications, and optional 5′ UTR, 3′ UTR, and IRES element concepts.
Claims Coverage
The consolidated claim coverage centers on a pharmaceutical composition comprising a synthetic CFTR-encoding polynucleotide assembled with a defined lipid composition. The independent coverage includes the CFTR-encoding synthetic polynucleotide with at least about 98% sequence identity to SEQ ID NO: 4 and three core lipid-component feature groups with specified molar percentage ranges.
CFTR-encoding synthetic polynucleotide with high sequence identity
A pharmaceutical composition comprising a synthetic polynucleotide assembled with a lipid composition, wherein the synthetic polynucleotide encodes a cystic fibrosis transmembrane conductance regulator (CFTR) protein and comprises a nucleic acid sequence having at least about 98% sequence identity to SEQ ID NO: 4.
Ionizable cationic lipid and separate SORT lipid
The lipid composition comprises an ionizable cationic lipid at a molar percentage of about 5% to about 30% and a selective organ targeting (SORT) lipid separate from the ionizable cationic lipid at a molar percentage of about 5% to about 30%.
Phospholipid, steroid or steroid derivative, and polymer-conjugated lipid
The lipid composition further comprises a phospholipid at a molar percentage of about 5% to about 25%, a steroid or steroid derivative at a molar percentage of about 15% to about 46%, and a polymer-conjugated lipid at a molar percentage of about 0.5% to about 10%.
Overall, the inventive coverage centers on assembling a CFTR-encoding synthetic polynucleotide, with at least about 98% sequence identity to SEQ ID NO: 4, with a multi-component lipid composition that includes an ionizable cationic lipid, a separate SORT lipid, a phospholipid, a steroid or steroid derivative, and a polymer-conjugated lipid at specified molar percentage ranges.
Stated Advantages
Enhances expression or activity of the CFTR protein encoded by the synthetic polynucleotide within a cell.
Targeted pulmonary delivery, including aerosol/nebulization and apical delivery, with enrichment in lung secretory/basal cell populations and reduction in non-secretory/ciliated expression.
Documented Applications
A pharmaceutical aerosol composition for delivering a synthetic polynucleotide encoding a CFTR protein.
Treatment of cystic fibrosis.
Treatment of chronic obstructive pulmonary disease (COPD).
Treatment of hereditary emphysema.
Targeted pulmonary delivery using aerosol/nebulization and apical delivery.
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