Compositions and methods for targeted delivery to cells
Inventors
Hennig, Mirko • Kharitonov, Vladimir • Wustman, Brandon A. • EBY, Jackson • Bhattacharjee, Rumpa
Assignees
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Publication Number
US-12121610-B2
Publication Date
2024-10-22
Expiration Date
Abstract
Described herein are compositions, kits, and methods for potent delivery to a cell of a subject. The cell can be of a particular cell type, such as a basal cell, a ciliated cell, or a secretory cell. In some cases, the cell can be a lung cell of a particular cell type. Also described herein are pharmaceutical compositions comprising a therapeutic or prophylactic agent assembled to a lipid composition. The lipid composition can comprise an ionizable cationic lipid, a phospholipid, and a selective organ targeting lipid. Further described herein are high-potency dosage forms of a therapeutic or prophylactic agent formulated with a lipid composition.
Core Innovation
The invention relates to a lipid nanoparticle composition for delivering a polynucleotide to lung cells in a subject. The lipid nanoparticle is an aerosol composition and comprises a polynucleotide, a dendrimer ionizable cationic lipid, ethylphosphocholine at a molar percentage from about 20% to about 65%, a phospholipid, cholesterol, and a polyethylene glycol-conjugated lipid.
The disclosure further provides SORT (selective organ targeting) lipid concepts and structural definitions for ionizable cationic lipid embodiments, including dendrimer/dendron frameworks, positively charged moieties, counterions, biodegradable linkers, and related structural formulas. Representative dendrimer ionizable cationic lipid variants and table-based examples are described, together with pharmaceutically acceptable salts.
The subject matter also includes broad chemical and payload concepts associated with polynucleotides, including stereoisomer coverage for polynucleotides, expression of tRNA to restore defective tRNA function, CRISPR-associated proteins and Cas proteins, guide polynucleotides, CRISPR RNPs, and polypeptide therapeutics. The compositions are used to preferentially deliver the composition to target organs such as the lung, including delivery to lung cells.
Claims Coverage
The independent claim coverage centers on an aerosolizable lipid nanoparticle composition for delivering a polynucleotide to lung cells in a subject. The inventive features consistently include the dendrimer ionizable cationic lipid, ethylphosphocholine at about 20% to about 65% molar percentage, phospholipid, cholesterol, and a polyethylene glycol-conjugated lipid, with dependent refinements narrowing the ethylphosphocholine species, polynucleotide class, and delivery context.
Aerosolizable lipid nanoparticle for lung-cell polynucleotide delivery
A lipid nanoparticle composition for delivering a polynucleotide to the lung cells in a subject, wherein the lipid nanoparticle composition is an aerosol composition.
Dendrimer ionizable cationic lipid in the nanoparticle
A lipid nanoparticle comprising a dendrimer ionizable cationic lipid as a component of the aerosol composition.
Ethylphosphocholine molar percentage range
Ethylphosphocholine at a molar percentage from about 20% to about 65%.
Defined lipid component set with phospholipid, cholesterol, and PEG-conjugated lipid
The lipid nanoparticle comprises a phospholipid, cholesterol, and a polyethylene glycol-conjugated lipid in combination with the polynucleotide and the dendrimer ionizable cationic lipid.
Preferential delivery to lung cells
The lipid nanoparticle composition is defined as preferentially delivering the polynucleotide to lung cells in the subject.
Specified polynucleotide classes and target
The polynucleotide is a small interfering RNA, a short hairpin RNA, or a microRNA, and messenger RNA includes a sequence encoding the cystic fibrosis transmembrane conductance regulator.
Overall, the claim coverage is directed to an aerosolizable lipid nanoparticle composition that combines a polynucleotide with a dendrimer ionizable cationic lipid and ethylphosphocholine in an about 20% to about 65% molar percentage range, together with phospholipid, cholesterol, and a polyethylene glycol-conjugated lipid, for delivery to lung cells in a subject.
Stated Advantages
Improved potency associated with greater therapeutic effect compared with reference lipids lacking selective organ targeting (SORT) lipid.
Greater proportion of lung epithelial/cell-type subsets delivered.
High-potency dosage forms requiring lower doses.
Greater plurality of lung cells delivered, including specified lung cell-type subsets.
Improved therapeutic effects in lung airway cell types versus a reference lipid composition.
Preferentially delivering the polynucleotide to lung cells in the subject.
Documented Applications
Aerosol composition for delivering a polynucleotide to lung cells in a subject.
Aerosolizable delivery of polynucleotide therapeutics to lung cells in a subject, including delivery to lung epithelial and multiple lung cell-type subsets.
Therapeutic or prophylactic delivery using the disclosed lipid nanoparticle composition with polynucleotide payloads.
Aerosol dosage forms for lung targeting using SORT lipids, including nebulized delivery methods.
High-potency lung-targeting aerosol and intravenous dosage forms for delivery to organ and lung.
Delivery of a polynucleotide to lung cells in a subject using an aerosol composition.
Providing an aerosol composition to deliver a polynucleotide to lung cells in a subject.
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