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-11801306-B2
Publication Date
2023-10-31
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 method for reducing the risk of coronary disease through reducing LDL cholesterol and/or triglyceride levels in a subject. The method administers to the subject a lipid nanoparticle that encapsulates a nucleic acid payload engineered so that, upon delivery into the subject’s cells, the payload generates a gene editor capable of modifying one or more genes involved in controlling or regulating LDL and/or triglyceride levels.
The lipid nanoparticle further comprises a compound of Formula (V) in which each A group is a N-acetylgalactosamine moiety and the A groups collectively comprise a receptor targeting ligand. The compound includes L1 through L10 and L12 as independently substituted or unsubstituted C1-C12 alkylene, heteroalkylene, alkenylene, or alkynylene, with L11 as a substituted or unsubstituted -(CH2CH2O)n- or -(OCH2CH2)n- segment.
R is a lipid, nucleic acid, amino acid, or protein, with m selected from 1 to 10 and n selected from 1 to 200. The described payload includes embodiments where the lipid nanoparticle comprises mRNA encoding one or more gene editor nucleases or base editors together with one or more guide RNAs, and the disclosure also refers to receptor-targeting N-acetylgalactosamine-containing lipid nanoparticle composition and nucleic-acid-encoded gene editing directed to genes controlling LDL and/or triglyceride levels.
Claims Coverage
The provided material identifies one independent claim. It contains two core inventive groupings: a lipid nanoparticle delivering an engineered nucleic-acid payload to generate a gene editor for modifying genes involved in controlling or regulating LDL and/or triglyceride levels, and a lipid nanoparticle comprising a Formula (V) compound with N-acetylgalactosamine moieties as receptor targeting ligands.
Coronary-disease risk reduction via lipid nanoparticle gene editing for LDL and/or triglyceride control
A method for reducing the risk of coronary disease by reducing LDL cholesterol and/or triglyceride levels in a subject by administering a lipid nanoparticle encapsulating a nucleic acid payload that, upon delivery into the subject’s cells, is engineered to generate a gene editor capable of modifying one or more genes involved in controlling or regulating LDL and/or triglyceride levels.
Lipid nanoparticle comprising a Formula (V) receptor targeting ligand with N-acetylgalactosamine moieties
The lipid nanoparticle further comprises 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, with L1-L10 and L12 defined by substituted or unsubstituted linker options, L11 selected from -(CH2CH2O)n- or -(OCH2CH2)n-, R selected as a lipid, nucleic acid, amino acid, or protein, and m and n defined as integer ranges.
The claim coverage centers on administering a lipid nanoparticle carrying an engineered nucleic-acid payload that generates a gene editor to modify genes controlling LDL and/or triglyceride levels, together with a Formula (V) compound bearing N-acetylgalactosamine moieties as a receptor targeting ligand.
Stated Advantages
Reducing the risk of coronary disease through the reduction of LDL cholesterol and/or triglyceride levels in a subject.
Improved liver delivery in LDLr deficient mammal and in a mammal lacking ApoE, compared to a corresponding lipid nanoparticle without the compound, with percent editing at least 50% higher.
Documented Applications
Reducing the risk of coronary disease in a subject by reducing LDL cholesterol and/or triglyceride levels using a lipid nanoparticle delivering an engineered nucleic-acid payload that generates a gene editor.
CRISPR/Cas gene-editing context for delivery to hepatocytes/liver cells and modification of genes involved in controlling or regulating LDL and/or triglyceride levels in a subject for reducing coronary disease risk [procedural detail omitted for safety].
Use in mammal models described in the provided claim summaries, including an LDLr deficient mammal and a mammal lacking ApoE, to assess improved liver delivery/editing measured by percent editing [procedural detail omitted for safety].
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