Compositions and methods for targeted RNA delivery
Inventors
Rajeev, Kallanthottathil G. • Kasiewicz, Lisa N. • Malyala, Padma • Biswas, Souvik
Assignees
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Publication Number
US-12569570-B2
Publication Date
2026-03-10
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.
Core Innovation
The invention provides a method of preparing GalNAc-lipid nanoparticles comprising one or more nucleic acid active agents, lipid excipients, and a GalNAc-lipid receptor targeting conjugate. The lipid excipients are selected from a sterol or derivative thereof, a phospholipid, a stealth lipid, and an amino lipid. The claimed preparation forms nanoparticles from aqueous and organic solutions; [procedural detail omitted for safety].
The GalNAc-lipid receptor targeting conjugate is selected from compounds of Formula (V) or Formula (VI), or pharmaceutically acceptable salts thereof, containing targeting groups linked to hydrophobic lipid anchors. The compositions enable ASGPR-mediated hepatocyte delivery of nucleic acid payloads, including guide RNA and mRNA encoding a gene editor nuclease or base editor. The background section and the problem being solved are not explicitly described in patent.
Claims Coverage
The relevant claims identify one independent claim directed to preparing GalNAc-lipid nanoparticles, comprising three inventive features.
GalNAc-lipid nanoparticle formulation
The nanoparticles comprise one or more nucleic acid active agents, one or more lipid excipients selected from a sterol or derivative thereof, a phospholipid, a stealth lipid, and an amino lipid, and a GalNAc-lipid receptor targeting conjugate.
Preparation of GalNAc-lipid nanoparticles
The method prepares GalNAc-LNPs by combining nucleic-acid-containing and lipid-containing solutions and incubating the mixture to form nanoparticles; [procedural detail omitted for safety].
GalNAc-lipid receptor targeting conjugate
The GalNAc-lipid receptor targeting conjugate is a compound of Formula (V) or Formula (VI), or a pharmaceutically acceptable salt thereof, with specified linker groups and structural options.
The independent claim covers a GalNAc-LNP formulation and its method of preparation combining nucleic acid active agents, specified lipid excipients, and a Formula (V) or Formula (VI) receptor targeting conjugate.
Stated Advantages
The disclosed approaches can improve GalNAc-lipid distribution, particle uniformity, and process control relative to post-addition.
The disclosed approaches can improve gene-editing efficacy relative to post-addition.
The disclosure identifies LDLR-independent delivery to hepatocytes and improved editing or target-protein reduction in LDLR-deficient models relative to non-targeted controls.
The reported results support delivery and biological activity of the GalNAc-LNP formulations across mouse and nonhuman-primate models.
Documented Applications
GalNAc/ASGPR-targeted delivery of nucleic acid active agents, including guide RNA and mRNA encoding a gene editor nuclease or base editor, to hepatocytes in vitro and in vivo.
Gene-editing applications targeting PCSK9 or ANGPTL3 in primary human hepatocytes.
In vivo gene editing and pharmacodynamic evaluations targeting PCSK9, ANGPTL3, and LDLR in mice, including LDL receptor-deficient and ApoE-deficient models, and nonhuman primates.
An ASGPR-based assay for evaluating surface GalNAc-lipid on GalNAc-LNPs.
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