Lipids for lipid nanoparticle delivery of active agents
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Publication Number
US-12151996-B2
Publication Date
2024-11-26
Expiration Date
Abstract
Compounds are provided having the following structure: or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R1, R2, R3, R4, R5, L1, L2, L3, G1, G2, and G3 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 inducing expression of a protein in a mammal by administering a lipid nanoparticle. The lipid nanoparticle comprises a compound having structure (I), and the compound is used as a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, together with an mRNA encoding the protein. Variant compound structures (IA) and (IB) are also disclosed, with defined substituent patterns for R1-R5, L1-L3, G1-G3, and an integer n greater than 0.
The disclosed lipid nanoparticles are used for delivery of therapeutic nucleic acids, including mRNA, antisense oligonucleotides, siRNA, miRNA inhibitors, and plasmid DNA, to induce protein expression or gene expression silencing. The document describes nucleic acid protection from serum degradation or clearance and mentions systemic versus local delivery contexts. Representative novel cationic lipid structures are presented together with lipid nanoparticle formulation concepts.
A key disclosed intent is improved in vivo activity and tolerability by using the cationic amino lipid compounds within lipid nanoparticles. Example biological outcomes include liver luciferase expression after intravenous tail-vein delivery of luciferase mRNA-LNPs, inducing protein expression such as erythropoietin mRNA-related red blood cell production, and protection against infection through antigen/antibody expression.
Claims Coverage
The independent claim covers a method for inducing expression of a protein in a mammal using a lipid nanoparticle comprising a compound of structure (I) together with an mRNA encoding the protein. Based on the provided partial claim content, only one independent claim is present.
Lipid nanoparticle containing a compound of structure (i) with mRNA encoding the protein
Administering to the mammal a lipid nanoparticle comprising a compound having structure (I), or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, together with an mRNA encoding the protein.
Structure (i) substituent and linkage constraints
The compound having structure (I) includes variable substituents R1-R5, linkers L1-L3, G1-G3, and an integer n greater than 0, with R1 optionally substituted C1-C24 alkyl or optionally substituted C2-C24 alkenyl; R2 and R3 each independently optionally substituted C1-C36 alkyl; R4 and R5 each independently optionally substituted C1-C6 alkyl, or R4 and R5 join with the nitrogen atom to form an optionally substituted heterocyclyl ring or optionally substituted heteroaryl ring; and G1, G2, and G3 selected from the claimed linkage options.
The claim coverage centers on administering an LNP that combines structure (I)-defined compound features with an mRNA encoding the protein to induce protein expression in a mammal.
Stated Advantages
Improved in vivo activity.
Improved tolerability.
Protection of nucleic acids from serum degradation and clearance.
Documented Applications
Inducing expression of a protein in a mammal using a lipid nanoparticle comprising a structure (I) compound and an mRNA encoding the protein.
Inducing protein expression for producing red blood cells via erythropoietin mRNA.
Protection against infection through antigen/antibody expression.
Liver luciferase expression after intravenous tail-vein delivery of luciferase mRNA-LNPs in a mammal, with reported luciferase activity measured in liver.
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