Lipids and lipid nanoparticle formulations for delivery of nucleic acids
Inventors
Ansell, Steven M. • Du, Xinyao
Assignees
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Publication Number
US-9737619-B2
Publication Date
2017-08-22
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 provides a pegylated lipid having structure (II), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof. In the structure (II), R10 and R11 are each independently a straight or branched, saturated or unsaturated alkyl chain containing from 10 to 30 carbon atoms, optionally interrupted by one or more ester bonds. The parameter z has a mean value ranging from 30 to 60, and the proviso excludes the case where R10 and R11 are both n-octadecyl when z is 42.
The pegylated lipid structure includes embodiments that further define z by particular mean values and narrow R10 and R11 through specific chain-length and substitution options. The disclosure also describes compositions combining the pegylated lipid with a cationic lipid and optionally neutral lipids such as DSPC, DPPC, DMPC, DOPC, POPC, DOPE, or SM, together with steroids such as cholesterol.
The described approach is directed to lipid nanoparticles that encapsulate or associate nucleic acids, including mRNA, antisense/siRNA, plasmids, and miRNA inhibitors. The pegylated lipid subset is used in nanoparticle compositions that protect the nucleic acid payload against serum nuclease degradation and enable intracellular delivery in vitro and in vivo, including suitability for systemic delivery.
Claims Coverage
The claim coverage centers on one independent pegylated-lipid structure definition, with multiple dependent claims refining the lipid parameters and further extending to compositions by adding a cationic lipid and optional components including cholesterol. Three inventive features are captured in the independent coverage, with additional dependent narrowing of z and R10/R11.
Pegylated lipid structure with constrained R10/R11 and mean z
A pegylated lipid having structure (II), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein R10 and R11 are each independently a straight or branched, saturated or unsaturated alkyl chain containing from 10 to 30 carbon atoms, optionally interrupted by one or more ester bonds, and z has a mean value ranging from 30 to 60, with the exclusion that R10 and R11 are not both n-octadecyl when z is 42.
Constrained mean z for the pegylated lipid
The pegylated lipid wherein z is about 45.
Straight saturated C12-C16 alkyl chains for R10 and R11
The pegylated lipid wherein R10 and R11 are each independently straight, saturated alkyl chains containing 12 to 16 carbon atoms each.
R10 and R11 set to 12 carbons with branching, saturation, or unsaturation options
The pegylated lipid wherein R10 and R11 are each independently straight or branched saturated or unsaturated alkyl chains containing 12 carbon atoms.
Composition includes a cationic lipid defined by specified structures
A composition including the pegylated lipid and a cationic lipid that has one of the specified cationic lipid chemical structures shown in the claim images.
Composition includes cholesterol as the steroid component
The composition wherein the steroid component is cholesterol.
Overall, the claim set is anchored by a pegylated lipid defined by R10/R11 alkyl-chain constraints and a mean PEG parameter z within 30 to 60, with an exclusion tied to z = 42 and the n-octadecyl case. Dependent refinements narrow the chain definitions and/or fix z, and later dependent claims extend to compositions that include a defined cationic lipid and specify cholesterol as the steroid component.
Stated Advantages
Protects nucleic acids against serum nuclease degradation.
Enables intracellular delivery in vitro and in vivo.
Suitability for systemic delivery.
A correlation between cationic lipid pKa and nucleic acid delivery effectiveness is described.
Unexpected advantage is noted for specific combinations highlighted in the liver luciferase expression results for multiple cationic lipids.
Therapeutic delivery of human FIX mRNA is described as generating clinically relevant hFIX plasma levels measured by ELISA, with duration of about 15 h or longer.
Documented Applications
Lipid nanoparticles for encapsulating or associating nucleic acids including mRNA, antisense/siRNA, plasmids, and miRNA inhibitors.
Use in vitro and in vivo to support intracellular delivery of nucleic acid payloads.
Systemic delivery of nucleic-acid-loaded lipid nanoparticles.
LNP-based nucleic acid delivery assessed by liver luciferase expression after tail vein injection, including comparisons across multiple cationic lipids.
In vivo expression kinetics assessed using cherry red mRNA, including PEG-lipid type comparisons between PEG-DMG and PEG-DMA.
Therapeutic delivery of human FIX mRNA to generate clinically relevant hFIX plasma levels measured by ELISA.
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