Lipids and lipid nanoparticle formulations for delivery of nucleic acids
Inventors
Ansell, Steven M. • Du, Xinyao
Assignees
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Publication Number
US-11634379-B2
Publication Date
2023-04-25
Expiration Date
Abstract
Compounds are provided having the following structure: or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein R1a, R1b, R2a, R2b, R3a, R3b, R4a, R4b, R5, R6, R7, R8, R9, L1, L2, a, b, c, d and e are as defined herein. Use of the compounds as a component of lipid nanoparticle formulations for delivery of a therapeutic agent, compositions comprising the compounds and methods for their use and preparation are also provided.
Core Innovation
The invention relates to a method for inducing expression of a protein in a subject by administering a lipid nanoparticle. The lipid nanoparticle comprises a compound having structure (II) and an mRNA encoding the protein. The compound of structure (II) includes R10 and R11, each independently a straight, saturated alkyl chain containing from 12 to 16 carbon atoms, and the PEG portion of structure (II) is selected such that it has an average molecular weight of about 2000 to 6000 g/mol.
In the described embodiments, parameter z is selected so that the PEG portion of structure (II) has an average molecular weight of about 2000 to 6000 g/mol, including a range of 30 to 60 and an average molecular weight of about 2500 g/mol in dependent claims. The lipid nanoparticle is further characterized by the presence of an mRNA encoding the protein, including mRNA encoding an antibody.
The specification describes pegylated lipid component structures, including structure (II), in combination with cationic lipid(s) of Formula (I), optional therapeutic nucleic acids, and neutral lipids such as DSPC, DPPC, DMPC, DOPC, POPC, DOPE, and SM, as well as cholesterol or steroid components. Molar ratio embodiments are provided for combining the compound, neutral lipid, cholesterol, and pegylated lipid components within lipid nanoparticle formulations.
Claims Coverage
The independent claim covers a method of inducing expression of a protein in a subject by administering a lipid nanoparticle with a structure (II) pegylated lipid compound defined by R10/R11 and PEG average molecular weight selection, and an mRNA encoding the protein. Dependent claims further narrow subject/protein and refine the lipid parameters.
Lipid nanoparticle with structure (II) compound and PEG molecular-weight selection
A lipid nanoparticle comprising a compound having structure (II) wherein R10 and R11 are each independently a straight, saturated alkyl chain containing from 12 to 16 carbon atoms, and z is selected such that the PEG portion of structure (II) has an average molecular weight of about 2000 to 6000 g/mol.
mRNA encoding the protein administered with the lipid nanoparticle
Administering, to the subject, the lipid nanoparticle comprising an mRNA encoding the protein.
Subject-restricted method for inducing expression
Dependent refinements characterize the method by narrowing the subject, including human, mammal, non-human primate, and liver expression.
Protein-specific encoding mRNA
Dependent refinements specify the encoded protein type, including mRNA encoding an antibody.
PEG z-range selection
Dependent refinements specify that parameter z takes values from 30 to 60.
PEG average molecular weight selection around 2500 g/mol
Dependent refinements specify that parameter z is chosen so the average molecular weight of structure (II) is about 2500 g/mol.
Alkyl chain carbon-number constraint
Dependent refinements specify that R10 and R11 are each straight, saturated alkyl chains containing 12 carbon atoms.
Across the independent claim and its dependents, the central claim coverage combines a lipid nanoparticle that includes a structure (II) pegylated lipid compound with defined R10/R11 straight, saturated alkyl chain carbon counts and a PEG average molecular weight selection via z, together with an mRNA encoding the protein. Dependent claims further specify subject/protein and tighten z and alkyl-chain parameter selections.
Stated Advantages
Improved activity and tolerability.
Increased therapeutic index.
Documented Applications
Delivering nucleic acids, including mRNA, antisense oligonucleotides, siRNA, plasmids, and miRNA inhibitors, for in vitro and in vivo modulation of gene and/or protein expression.
Methods of inducing expression of a protein in a subject by administering lipid nanoparticles comprising the specified pegylated lipid structure (II) and mRNA encoding the protein.
In vivo liver expression after administering lipid nanoparticle formulations via tail-vein delivery, including luciferase expression correlated with pKa and different hydrocarbon chain structures/headgroup chain lengths.
In vivo expression of cherry red fluorescent protein mRNA in homogeneous liver expression after LNP delivery.
Therapeutic hFIX protein levels in mouse plasma after LNP delivery using cationic lipids.
Inducing expression of proteins with pharmacological effect including increasing the production of red blood cells.
Using mRNA encoding an antibody as the payload in the lipid nanoparticle for induced expression.
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