Compositions and methods for targeted RNA delivery
Inventors
Rajeev, Kallanthottathil G. • Biswas, Souvik • Malyala, Padma • Kasiewicz, Lisa N. • Chadwick, Alexandra • Reiss, Caroline
Assignees
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Publication Number
US-11207416-B2
Publication Date
2021-12-28
Expiration Date
Abstract
Provided herein are compositions, methods of making the same, and methods for targeted delivery of therapeutic agents for modifying expression and function of target genes, e.g. proteins involved in lipid and cholesterol metabolism such as PCSK9. Further provided herein are compositions and methods of treating conditions related to coronary disease.
Core Innovation
The invention relates to a receptor targeting conjugate comprising a compound of Formula (V), wherein a plurality of A groups collectively comprise a receptor targeting ligand and each A group is a N-acetylgalactosamine moiety. The conjugate includes linker segments L1 through L12 that are independently substituted or unsubstituted according to defined alkylene, heteroalkylene, alkenylene, alkynylene, ether, thioether, sulfoxide, sulfone, phosphate, carbonyl, amide, urea, and phosphoramidate-like linkage options, and L11 is substituted or unsubstituted (CH2CH2O)n or (OCH2CH2)n.
The compound further defines R as a lipid, nucleic acid, amino acid, protein, or lipid nanoparticle, with m selected from 1 to 10 and n selected from 1 to 200. The disclosure also presents representative GalNAc-conjugated receptor-targeting lipids and GalNAc-lipid nanoparticles, including lipid nanoparticle compositions that include nucleic acid payloads such as mRNA and guide RNA for gene editing and base editing components.
The described subject matter further associates GalNAc-modified gRNA conjugates with stable, liver-specific delivery and maintained CRISPR activity, and also describes LNP manufacturing approaches for adding the GalNAc-lipid, including inline mixing and split addition concepts. The disclosure includes pharmaceutical compositions comprising the nanoparticle compositions together with an excipient or carrier.
Claims Coverage
The independent claim coverage centers on one receptor targeting conjugate of Formula (V) with N-acetylgalactosamine A groups, defined linker segments L1–L12, a variable R group, and bounded integers m and n. Five inventive features are captured across the consolidated claim set.
Formula (V) receptor targeting conjugate with N-acetylgalactosamine A groups
A receptor targeting conjugate comprising a compound of Formula (V) wherein a plurality of the A groups collectively comprise a receptor targeting ligand and each A group is a N-acetylgalactosamine moiety.
Defined linker segments L1–L12
Linker segments L1, L2, L3, L4, L5, L6, L7, L8, L9, L10, and L12 are independently substituted or unsubstituted according to the disclosed structural options, and L11 is substituted or unsubstituted (CH2CH2O)n or (OCH2CH2)n.
Variable substituent R
R is selected from a lipid, nucleic acid, amino acid, protein, or lipid nanoparticle.
Bounded integer parameters m and n
m is an integer selected from 1 to 10 and n is an integer selected from 1 to 200.
Nanoparticle and pharmaceutical compositions
A nanoparticle composition includes mRNA and/or guide RNA encoding gene editor nuclease and/or base editor nuclease, and a pharmaceutical composition includes the nanoparticle composition together with an excipient or carrier.
The claim coverage is directed to a Formula (V) receptor targeting conjugate built from N-acetylgalactosamine A groups, defined linker segments, and an R group selected from lipid, nucleic acid, amino acid, protein, or lipid nanoparticle, with dependent coverage extending to nanoparticle compositions containing mRNA and/or guide RNA and to pharmaceutical compositions including an excipient or carrier.
Stated Advantages
More homogeneous GalNAc distribution.
Improved particle uniformity.
Improved editing efficacy.
Stable, liver-specific delivery.
Maintained CRISPR activity.
Serum nuclease protection for fully encapsulated RNAs.
Documented Applications
Lipid nanoparticle compositions comprising receptor targeting conjugate (GalNAc-lipid) and nucleic acid payloads for CRISPR editing, including gene editor nuclease and base editor nuclease with mRNA and guide RNA.
Pharmaceutical compositions comprising the nanoparticle compositions with an excipient or carrier.
Targeted delivery of therapeutic nucleic acids using guide RNA and guide RNA–Cas complexes, including guide RNA–Cas9.
Molecular profiling involving tissues, cells, nucleic acids, gene fragments, and expression products.
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