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Publication Number
US-12024484-B2
Publication Date
2024-07-02
Expiration Date
Abstract
The present disclosure relates to PEG-lipids, cationic and/or ionizable lipids and nucleic acid-lipid particle compositions comprising the same. The present disclosure also relates to methods of making, using and delivering the described lipids and lipid-containing particles.
Core Innovation
The disclosure relates to amino lipid structures of Formula (I*) and Formula (II*), including pharmaceutically acceptable salt or solvate forms. The amino lipid structures define broad substituent choices through R1, R2, R3, X, Y, Z, L, R4, R5, R6, Cy, R7, R8, R9, R10, R11, and indices n, m, q, a, and b, within specified chemical classes or integer ranges. The disclosure also includes PEG lipid structures of Formula (III*) with defined substituents R21, R22, R26, R27, R28, R23, R24, R25, and integer parameters k1 through k4.
The amino lipid embodiments include long hydrocarbon and hetero-hydrocarbon substituents, alkylene-L-R6 and alkenylene-L-R6 motifs, and multiple carbonyl-, oxygen-, nitrogen-, and sulfur-containing linkage forms. The PEG lipid embodiments include amide, ester, ether, and thioester-like linkage alternatives and PEG-linked architectures defined by repeating ether-oxygen segments and terminal group options. The disclosure also presents image-based representative structures and named lipid variants, including amino lipid, PEG lipid, and linked-lipid families with specified parameter ranges.
The content further describes nanoparticle compositions comprising an amino lipid selected from specified structures, with m constrained to 1 through 10. The disclosed structural classes are presented as lipid nanoparticle-related and PEG-lipid-related scaffolds, including examples identified as constituent lipid nanoparticles and LNP compositions. The examples are stated to correspond to the claimed formula-based lipid families.
Claims Coverage
The consolidated independent claims cover four inventive features: amino lipid of Formula (I*), amino lipid of Formula (II*), nanoparticle composition comprising selected amino lipid structures with m from 1 through 10, and PEG lipid of Formula (III*). Together, the claims define formula-based lipid scaffolds through enumerated substituent classes, linkage options, and integer parameters.
Amino lipid of Formula (I*)
An amino lipid having a structure of Formula (I*), or a pharmaceutically acceptable salt or solvate thereof, with R1 and R2 independently selected from hydrogen or specified C3-C30 alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, alkylene-L-R6, and alkenylene-L-R6 options; X, Y, and Z independently selected from C(O)-, NR4-, OC(O)-, OC(O)O-, and related oxygen-, nitrogen-, or sulfur-containing linkage groups or a bond; L independently selected from specified carbonyl, amide, ester, sulfide, oxygen, and related linker classes or a bond; and additional variables R3, R4, R5, R6, Cy, R7, R8, R9, R10, R11, and indices n, m, and q within the stated classes and ranges.
Amino lipid of Formula (II*)
An amino lipid having a structure of Formula (II*), or a pharmaceutically acceptable salt or solvate thereof, with R1 and R2 independently selected from hydrogen or specified C3-C30 alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, alkylene-L-R6, and alkenylene-L-R6 options; X, Y, and Z independently selected from C(O)-, NR4-, OC(O)-, OC(O)O-, and related oxygen-, nitrogen-, or sulfur-containing linkage groups or a bond; L independently selected from specified carbonyl, amide, ester, thioester, sulfide, oxygen, and related linker classes or a bond; and additional variables R3, R4, R6, Cy, R7, R8, a, b, and m within the stated classes and ranges.
Nanoparticle composition comprising selected amino lipid structures
A nanoparticle composition that comprises an amino lipid having a structure selected from specified structures, wherein m is 1 through 10, or a pharmaceutically acceptable salt or solvate thereof.
PEG lipid of Formula (III*)
A PEG lipid having the structure of Formula (III*) or Formula (III/III*), or a pharmaceutically acceptable salt or solvate thereof, with R21 and R22 independently selected from hydrogen or specified C1-C30 alkyl, C3-C30 alkenyl, or C3-C30 alkynyl options; R26, R27, and R28 independently selected from specified amide-, ester-, ether-, and thioester-like linkage classes and related variants; and additional parameters R4, R23, R24, R25, k1, k2, k3, and k4 within the stated constraints.
The claim coverage is centered on formula-defined amino lipids with broad substituent and linker definitions, a nanoparticle composition limited by selected amino lipid structures with m from 1 through 10, and a PEG lipid of Formula (III*) defined by enumerated linkage chemistry and integer parameter constraints.
Stated Advantages
Potential metabolic advantages, including deuteration for metabolic stability and increased half-life.
Substantially non-toxic LNPs are described.
Documented Applications
Constituting lipid nanoparticles (LNPs) using amino lipids and excipients as described in amino lipid Table 1B.
LNP formulation including PEG-lipid components.
Delivery of therapeutic agent payloads including nucleic acids, including mRNA, siRNA, miRNA, DNA, and RNA, including modified nucleic acids and isolated or purified nucleic acids.
Nanoparticle/LNP-type compositions are described as comprising LNPs, liposomes, and lipoplexes.
Delivery and gene editing using nucleic-acid lipid nanoparticle (LNP) compositions comprising PEG-lipids and amino lipids.
Gene editing targets including PCSK9 and ANGPTL3.
Use in base editing categories including CBE and ABE, and nuclease-related example involving SpCas9 mRNA.
Lipid nanoparticle-related composition contexts are documented by a Table 1B listing amino lipids and excipients for lipid nanoparticles.
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