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Gene editing of pcsk9 or angptl3 and compositions and methods of using same for … — Verve Therapeutics, Inc. (US20240390520A1)

Verve Therapeutics, Inc. · Google Patents

Google Patents · Patents

en google-patents intellectual-property patent

A method for treating or preventing an atherosclerotic cardiovascular disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the hybrid guide nucleic acid of claim 220 , the in vivo hybrid guide gene editing system of claim 234 , Gene editing of pcsk9 or angptl3 and compositions and methods of using same for … — Verve Therapeutics, Inc. (US20240390520A1)

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ABSTRACT

Abstract

Disclosed herein are novel gene editing systems capable of being delivered to a subject intravenously through a lipid nano particle pharmaceutical formulation and producing durable in vivo editing of a target gene, such as ANGPTL3, with high on-target gene editing efficiency, reduced or low off-target effect, and no germline editing. The gene editing systems comprise a chemically modified guide nucleic acid sequence with a spacer having a specified arrangement of deoxyribonucleotides and ribonucleotides. The novel gene editing systems comprise mRNA that encodes the gene editor proteins, which may include a modified nickase component. Methods of disease treatments using the gene editing systems are also disclosed.

Description

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of International Application No. PCT/US2022/044453, filed Sep. 22, 2022 which claims benefit under 35 U.S.C. Â§ 119 from Provisional Application Ser. No. 63/247,236, filed Sep. 22, 2021; Provisional Application Ser. No. 63/255,333, filed Oct. 13, 2021; and Provisional Application Ser. No. 63/389,679, filed Jul. 15, 2022, the disclosures of which each are incorporated herein by reference in their entirety.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has been submitted electronically in XML format and is hereby incorporated by reference by its entirety. Said XML copy, created Aug. 2, 2024, is named 53989-715.301 Replacement_SL_.xml and is 6,731,884 bytes in size.

SUMMARY OF THE INVENTION

Described herein is an in vivo hybrid guide gene editing system comprising: (a) a gene editor protein or a component thereof comprising a nucleic acid binding domain, or a nucleic acid encoding the gene editor protein or the component thereof; and (b) a hybrid guide nucleic acid comprising (i) a spacer sequence comprising a deoxyribonucleotide and a ribonucleotide comprising a ribose, wherein a 2â² hydroxyl group of the ribose is covalently linked to a methyl group (2â²-OMe), and (ii) a binding scaffold for the gene editor protein or component thereof, wherein (a) and (b) are constituent components of a pharmaceutical composition that comprises a lipid nanoparticle (LNP) containing (a) or (b), wherein the LNP comprises an amino lipid, a phospholipid, a sterol and a PEG lipid. In some embodiments, the spacer sequence corresponds to a protospacer on a target gene, and wherein the target gene is ANGPTL3. In some embodiments, the gene editor protein or the component thereof comprises a deaminase.

Described herein is an in vivo hybrid guide gene editing system comprising: (a) a gene editor protein or a component thereof comprising a nucleic acid binding domain, or a nucleic acid encoding the gene editor protein or the component thereof; and (b) a hybrid guide nucleic acid comprising (i) a spacer sequence comprising a deoxyribonucleotide and a ribonucleotide, wherein the spacer sequence corresponds to a protospacer on an ANGPTL3 gene, and (ii) a binding scaffold for the gene editor protein or component thereof, wherein (a) and (b) are constituent components of a pharmaceutical composition that comprises a lipid nanoparticle (LNP) containing (a) or (b), wherein the LNP comprises an amino lipid, a phospholipid, a sterol and a PEG lipid. In some embodiments, the gene editor protein or the component thereof comprises a deaminase. In some embodiments, the ribonucleotide comprises a ribose, and wherein the ribose comprises a 2â² hydroxyl group covalently linked to a methyl group (2â²-OMe).

Described herein is an in vivo hybrid guide gene editing system comprising: (a) a gene editor protein or a component thereof comprising a nucleic acid binding domain and a deaminase, or a nucleic acid encoding the gene editor protein or the component thereof; and (b) a hybrid guide nucleic acid comprising (i) a spacer sequence comprising a deoxyribonucleotide and a ribonucleotide, and (ii) a binding scaffold for the gene editor protein or component thereof, wherein (a) and (b) are constituent components of a pharmaceutical composition that comprises a lipid nanoparticle (LNP) containing (a) or (b), wherein the LNP comprises an amino lipid, a phospholipid, a sterol and a PEG lipid. In some embodiments, the spacer sequence corresponds to a protospacer on a target gene, and wherein the target gene is ANGPTL3. In some embodiments, the ribonucleotide comprises a ribose, and wherein the ribose comprises a 2â² hydroxyl group covalently linked to a methyl group (2â²-OMe).

In some embodiments, the spacer sequence comprises an unmodified ribonucleotide. In some embodiments, wherein the nucleic acid encoding the gene editor protein or the component thereof is an mRNA. In some embodiments, the gene editor protein or the component thereof comprises a single fusion protein or two or more proteins. In some embodiments, the spacer sequence comprises a phosphorothioate backbone modification (PS). In some embodiments, the spacer sequence comprises a (2â²-OMe)PS(2â²-OMe)PS(DNA)PS(DNA)(RNA)(DNA)(DNA)(DNA) motif. In some embodiments, the (2â²-OMe)PS(2â²-OMe)PS(DNA)PS(DNA)(RNA)(DNA)(DNA)(DNA) motif is located at the 5â² end of the spacer sequence. In some embodiments, the spacer sequence comprises a sequence with at least about 80%, about 90%, about 95%, about 99%, about 99.5%, or about 100% sequence identity or sequence similarity of SEQ ID NO: 30 or 31. In some embodiments, the spacer sequence comprises a (2â²-OMe)PS(2â²-OMe)PS(DNA)PS(DNA)(RNA)(DNA)(DNA) motif. In some embodiments, the (2â²-OMe)PS(2â²-OMe)PS(DNA)PS(DNA)(RNA)(DNA)(DNA) motif is located at the 5â² end of the spacer sequence. In some embodiments, the spacer sequence comprises a sequence with at least about 80%, about 90%, about 95%, about 99%, about 99.5%, or about 100% sequence identity or sequence similarity of SEQ ID NO: 28 or 29. In some embodiments, the spacer sequence comprises a (2â²-OMe)PS(2â²-OMe)PS(DNA)PS(DNA)(DNA)(DNA)(DNA) motif. In some embodiments, the (2â²-OMe)PS(2â²-OMe)PS(DNA)PS(DNA)(DNA)(DNA)(DNA) motif is located at the 5â² end of the spacer sequence. In some embodiments, the spacer sequence comprises a sequence with at least about 80%, about 90%, about 95%, about 99%, about 99.5%, or about 100% sequence identity or sequence similarity of SEQ ID NO: 5, 11 or 12. In some embodiments, the hybrid guide nucleic acid comprises a sequence with at least about 80%, about 90%, about 95%, about 99%, about 99.5%, or about 100% sequence identity or sequence similarity of a sequence selected from the group consisting of SEQ ID Nos: 110-113. In some embodiments, the hybrid guide nucleic acid comprises a sequence with at least about 80%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, or about 100% sequence identity or sequence similarity of a sequence selected from the group consisting of SEQ ID Nos: 106-109. In some embodiments, the guide nucleic acid comprises a sequence with at least about 80%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, or about 100% sequence identity or sequence similarity of a sequence selected from the group consisting of SEQ ID Nos: 79-82.

In some embodiments, the nucleic acid binding domain is capable of binding to DNA. In some embodiments, the nucleic acid binding domain is capable of binding to RNA. In some embodiments, the deoxyribonucleotide is located on

position

3, 4, 6, 7 or 8 from the 5â² end of the spacer sequence. In some embodiments, the spacer sequence comprises deoxyribonucleotides on

positions

3, 4, 6 and 7 from the 5â² end of the spacer sequence. In some embodiments, the spacer sequence comprises deoxyribonucleotides on positions 3 and 4 from the 5â² end of the spacer sequence. In some embodiments, the spacer sequence comprises deoxyribonucleotides on positions 6 and 7 from the 5â² end of the spacer sequence. In some embodiments, the spacer sequence comprises deoxyribonucleotides on

positions

3, 4, 6, 7 and 8 from the 5â² end of the spacer sequence. In some embodiments, the spacer sequence comprises one to ten deoxyribonucleotides. In some embodiments, the spacer sequence comprises one to five deoxyribonucleotides. In some embodiments, the DNA binding domain comprises a CRISPR protein or a fragment thereof. In some embodiments, the DNA binding domain comprises a catalytically impaired nuclease. In some embodiments, the DNA binding domain comprises a prime editing protein or a fragment thereof.

In some embodiments, the gene editor protein or the component thereof affects less than about 10%, about 9%, about 8%, about 7%, about 6%, about 5%, about 4%, about 3%, about 2%, or about 1% editing on all off-target sites as compared to a gene editing system comprising a corresponding gRNA without the deoxyribonucleotide. In some embodiments, the gene editor protein or the component thereof affects over about 50%, about 60%, about 70%, about 80%, about 90%, or about 95% editing on the target gene as compared to a gene editing system comprising a corresponding gRNA without the deoxyribonucleotide. In some embodiments, the gene editor protein or the component thereof affects over about 95%, about 96%, about 97%, about 98%, or about 99% editing on the target gene as compared to a gene editing system comprising a corresponding gRNA without the deoxyribonucleotide. In some embodiments, the gene editor protein or the component thereof affects from about 95% to about 99% editing on the target gene as compared to a gene editing system comprising a corresponding gRNA without the deoxyribonucleotide. In some embodiments, the LNP comprises a N-acetylgalactosamine (GalNAc) lipid receptor targeting conjugate. In some embodiments, the target gene is expressed in liver, or cells or tissues of liver origin. In some embodiments, the target gene is expressed in a non-liver organ or cells or tissues of non-liver origin.

Described herein is a method for treating or preventing an atherosclerotic cardiovascular disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the in vivo hybrid guide gene editing system described herein. In some embodiments, the subject is a primate. In some embodiments, the primate is human.

Described herein is a gene editing system comprising: (a) a gene editor protein or a component thereof comprising a nucleic acid binding domain, or a nucleic acid encoding the gene editor protein or the component thereof; and (b) a hybrid guide nucleic acid comprising a spacer sequence, wherein the spacer sequence comprises a deoxyribonucleotide and a ribonucleotide comprising a ribose, and wherein a 2â² hydroxyl group of the ribose is covalently linked to a methyl group (2â²-OMe).

Described herein is a gene editing system comprising: (a) a gene editor protein or a component thereof comprising a nucleic acid binding domain, or a nucleic acid encoding the gene editor protein or the component thereof; and (b) a hybrid guide nucleic acid comprising a spacer sequence, wherein the spacer sequence comprises a deoxyribonucleotide and a ribonucleotide, and wherein the spacer sequence corresponds to a protospacer on an ANGPTL3 gene.

Described herein is a gene editing system comprising: (a) a gene editor protein or a component thereof comprising a nucleic acid binding domain and a deaminase, or a nucleic acid encoding the gene editor protein or the component thereof, and (b) a hybrid guide nucleic acid comprising a spacer sequence, wherein the spacer sequence comprises a deoxyribonucleotide and a ribonucleotide.

Described herein is a hybrid guide nucleic acid for a gene editing system, wherein the hybrid guide comprises (i) a spacer sequence comprising a deoxyribonucleotide and a ribonucleotide comprising a ribose, wherein a 2â² hydroxyl group of the ribose is covalently linked to a methyl group (2â²-OMe), and (ii) a binding scaffold. In some embodiments, the spacer sequence comprises a (2â²-OMe)PS(2â²-OMe)PS(DNA)PS(DNA)(RNA)(DNA)(DNA)(DNA) motif. In some embodiments, the (2â²-OMe)PS(2â²-OMe)PS(DNA)PS(DNA)(RNA)(DNA)(DNA)(DNA) motif is located at the 5â² end of the spacer sequence. In some embodiments, the spacer sequence comprises a sequence with at least about 80%, about 90%, about 95%, about 99%, about 99.5%, or about 100% sequence identity or sequence similarity of SEQ ID NO: 30 or 31. In some embodiments, the spacer sequence comprises a (2â²-OMe)PS(2â²-OMe)PS(DNA)PS(DNA)(RNA)(DNA)(DNA) motif. In some embodiments, the (2â²-OMe)PS(2â²-OMe)PS(DNA)PS(DNA)(RNA)(DNA)(DNA) motif is located at the 5â² end of the spacer sequence. In some embodiments, the spacer sequence comprises a sequence with at least about 80%, about 90%, about 95%, about 99%, about 99.5%, or about 100% sequence identity or sequence similarity of SEQ ID NO: 28 or 29. In some embodiments, the spacer sequence comprises a (2â²-OMe)PS(2â²-OMe)PS(DNA)PS(DNA)(DNA)(DNA)(DNA) motif. In some embodiments, the (2â²-OMe)PS(2â²-OMe)PS(DNA)PS(DNA)(DNA)(DNA)(DNA) motif is located at the 5â² end of the spacer sequence. In some embodiments, the spacer sequence comprises a sequence with at least about 80%, about 90%, about 95%, about 99%, about 99.5%, or about 100% sequence identity or sequence similarity of SEQ ID NO: 5, 11 or 12. In some embodiments, the hybrid guide nucleic acid comprises a sequence with at least about 80%, about 90%, about 95%, about 99%, about 99.5%, or about 100% sequence identity or sequence similarity of a sequence selected from the group consisting of SEQ ID Nos: 110-113. In some embodiments, the hybrid guide nucleic acid comprises a sequence with at least about 80%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, or about 100% sequence identity or sequence similarity of a sequence selected from the group consisting of SEQ ID Nos: 106-109. In some embodiments, the guide nucleic acid comprises a sequence with at least about 80%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, or about 100% sequence identity or sequence similarity of a sequence selected from the group consisting of SEQ ID Nos: 79-82.

CROSS REFERENCE TO RELATED APPLICATIONS

SEQUENCE LISTING

SUMMARY OF THE INVENTION

Described herein is an in vivo hybrid guide gene editing system comprising: (a) a gene editor protein or a component thereof comprising a nucleic acid binding domain, or a nucleic acid encoding the gene editor protein or the component thereof; and (b) a hybrid guide nucleic acid comprising (i) a spacer sequence comprising a deoxyribonucleotide and a ribonucleotide, wherein the spacer sequence corresponds to a protospacer on an ANGPTL3 gene, and (ii) a binding scaffold for the gene editor protein or component thereof, wherein (a) and (b) are constituent components of a pharmaceutical composition that comprises a lipid nanoparticle (LNP) containing (a) or (b), wherein the LNP comprises an amino lipid, a phospholipid, a sterol and a PEG lipid. In some embodiments, the gene editor protein or the component thereof comprises a deaminase. In some embodiments, the ribonucleotide comprises a ribose, and wherein the ribose comprises a 2â² hydroxyl group covalently linked to a methyl group (2â²-OMe).

position

3, 4, 6, 7 or 8 from the 5â² end of the spacer sequence. In some embodiments, the spacer sequence comprises deoxyribonucleotides on

positions

Described herein is a gene editing system comprising: (a) a gene editor protein or a component thereof comprising a nucleic acid binding domain, or a nucleic acid encoding the gene editor protein or the component thereof; and (b) a hybrid guide nucleic acid comprising a spacer sequence, wherein the spacer sequence comprises a deoxyribonucleotide and a ribonucleotide, and wherein the spacer sequence corresponds to a protospacer on an ANGPTL3 gene.

Described herein is a composition comprising a Cas9 nickase, wherein the Cas9 nickase comprises a mutation, and wherein the mutation is selected from the group consisting of: N692A, M694A, Q695A, H698A, K810A, K855A, K848A, K1003A, R1060A as compared to a Cas9 nickase of SEQ ID NO: 695 In some embodiments, the Cas9 nickase comprises a sequence with at least 90% identity to SEQ ID NO: 695. In some embodiments, the Cas9 nickase comprises a sequence with at least 95% identity to SEQ ID NO: 695. In some embodiments, the Cas9 nickase comprises a sequence with at least 98% identity to SEQ ID NO: 695. In some embodiments, the Cas9 nickase comprises a sequence with at least 99% identity to SEQ ID NO: 695. In some embodiments, the Cas9 nickase comprises a sequence with at least 99.5% identity to SEQ ID NO: 695. In some embodiments, the mutation comprises N692A, M694A, Q695A and H698A as compared to the Cas9 nickase of SEQ ID NO: 695. In some embodiments, the mutation comprises K855A as compared to the Cas9 nickase of SEQ ID NO: 695. In some embodiments, the mutation comprises K848A, K1003A and R1060A as compared to the Cas9 nickase of SEQ ID NO: 695. In some embodiments, the mutation comprises K810A, K1003A, R1060A as compared to the Cas9 nickase of SEQ ID NO: 695.

Described herein is a composition comprising a nucleic acid encoding a Cas9 nickase, wherein the nucleic acid encoding the Cas9 nickase comprises a mutation, and wherein the mutation is selected from the group consisting of: AAC at codon 692 is mutated to GCC, AUG at codon 694 is mutated to GCC, CAG at codon 695 is mutated to GCC, CAC at codon 698 is mutated to GCC, AAG at codon 855 is mutated to GCC, AAG at codon 810 is mutated to GCC, AAG at codon 848 is mutated to GCC, AAG at codon 1003 is mutated to GCC, and CGG at codon 1060 is mutated to GCC as compared to a nucleic acid of SEQ ID NO: 694. In some embodiments, the nucleic acid encoding the Cas9 nickase comprises a sequence with at least 90% identity to SEQ ID NO: 694. In some embodiments, the nucleic acid encoding the Cas9 nickase comprises a sequence with at least 95% identity to SEQ ID NO: 694. In some embodiments, the nucleic acid encoding the Cas9 nickase comprises a sequence with at least 98% identity to SEQ ID NO: 694. In some embodiments, the nucleic acid encoding the Cas9 nickase comprises a sequence with at least 99% identity to SEQ ID NO: 694. In some embodiments, the nucleic acid encoding the Cas9 nickase comprises a sequence with at least 99.5% identity to SEQ ID NO: 694. In some embodiments, the mutation comprises AAC at codon 692 is mutated to GCC, AUG at codon 694 is mutated to GCC, CAG at codon 695 is mutated to GCC and CAC at codon 698 is mutated to GCC as compared to the nucleic acid SEQ ID NO: 694. In some embodiments, the mutation comprises AAG at codon 855 is mutated to GCC as compared to the nucleic acid SEQ ID NO: 694. In some embodiments, the mutation comprises AAG at codon 878 is mutated to GCC, AAG at codon 1003 is mutated to GCC, and CGG at codon 1060 is mutated to GCC as compared to the nucleic acid SEQ ID NO: 694. In some embodiments, the mutation comprises AAG at codon 810 is mutated to GCC, AAG at codon 1003 is mutated to GCC, and CGG at codon 1060 is mutated to GCC as compared to the nucleic acid SEQ ID NO: 694.

Described herein is a gene editing system comprising: (a) a Cas9 nickase, and (b) a guide RNA comprising a spacer corresponding to protospacer sequence on a target gene and a binding scaffold for the Cas9 nickase, wherein the Cas9 nickase comprises a mutation, wherein the mutation is selected from the group consisting of: N692A, M694A, Q695A, H698A, K810A, K855A, K848A, K1003A, R1060A as compared to a Cas9 nickase of SEQ ID NO: 695. In some embodiments, the gene editing system comprises a deaminase. In some embodiments, the gene editing system comprises a polymerase. In some embodiments, the polymerase is a reverse transcriptase. In some embodiments, the target gene is PCSK9. In some embodiments, the target gene is ANGPTL3. In some embodiments, the Cas9 nickase comprises a sequence with at least 90% identity to SEQ ID NO: 695. In some embodiments, the Cas9 nickase comprises a sequence with at least 95% identity to SEQ ID NO: 695. In some embodiments, the Cas9 nickase comprises a sequence with at least 98% identity to SEQ ID NO: 695. In some embodiments, the Cas9 nickase comprises a sequence with at least 99% identity to SEQ ID NO: 695. In some embodiments, the Cas9 nickase comprises a sequence with at least 99.5% identity to SEQ ID NO: 695. In some embodiments, the mutation comprises N692A, M694A, Q695A and H698A as compared to the Cas9 nickase of SEQ ID NO: 695. In some embodiments, the mutation comprises K855A as compared to the Cas9 nickase of SEQ ID NO: 695. In some embodiments, the mutation comprises K848A, K1003A and R1060A as compared to the Cas9 nickase of SEQ ID NO: 695. In some embodiments, the mutation comprises K810A, K1003A, R1060A as compared to the Cas9 nickase of SEQ ID NO: 695.

Described herein is a gene editing system comprising: (a) a nucleic acid encoding a Cas9 nickase, and (b) a guide RNA comprising a spacer corresponding to protospacer sequence on a target gene and a binding scaffold for the Cas9 nickase, wherein the nucleic acid encoding the Cas9 nickase comprises a mutation, wherein the mutation is selected from the group consisting of: AAC at codon 692 is mutated to GCC, AUG at codon 694 is mutated to GCC, CAG at codon 695 is mutated to GCC, CAC at codon 698 is mutated to GCC, AAG at codon 855 is mutated to GCC, AAG at codon 810 is mutated to GCC, AAG at codon 848 is mutated to GCC, AAG at codon 1003 is mutated to GCC, and CGG at codon 1060 is mutated to GCC as compared to a nucleic acid of SEQ ID NO: 694. In some embodiments, the gene editing system comprises a nucleic acid encoding a deaminase. In some embodiments, the gene editing system comprises a nucleic acid encoding a polymerase. In some embodiments, the polymerase is a reverse transcriptase. In some embodiments, the target gene is PCSK9. In some embodiments, the target gene is ANGPTL3. In some embodiments, the nucleic acid encoding the Cas9 nickase comprises a sequence with at least 90% identity to SEQ ID NO: 694. In some embodiments, the nucleic acid encoding the Cas9 nickase comprises a sequence with at least 95% identity to SEQ ID NO: 694. In some embodiments, the nucleic acid encoding the Cas9 nickase comprises a sequence with at least 98% identity to SEQ ID NO: 694. In some embodiments, the nucleic acid encoding the Cas9 nickase comprises a sequence with at least 99% identity to SEQ ID NO: 694. In some embodiments, the nucleic acid encoding the Cas9 nickase comprises a sequence with at least 99.5% identity to SEQ ID NO: 694. In some embodiments, the mutation comprises AAC at codon 692 is mutated to GCC, AUG at codon 694 is mutated to GCC, CAG at codon 695 is mutated to GCC and CAC at codon 698 is mutated to GCC as compared to the nucleic acid SEQ ID NO: 694. In some embodiments, the mutation comprises AAG at codon 855 is mutated to GCC as compared to the nucleic acid SEQ ID NO: 694. In some embodiments, the mutation comprises AAG at codon 878 is mutated to GCC, AAG at codon 1003 is mutated to GCC, and CGG at codon 1060 is mutated to GCC as compared to the nucleic acid SEQ ID NO: 694. In some embodiments, the mutation comprises AAG at codon 810 is mutated to GCC, AAG at codon 1003 is mutated to GCC, and CGG at codon 1060 is mutated to GCC as compared to the nucleic acid SEQ ID NO: 694.

Described herein is a nucleic acid comprises a sequence selected from the group consisting of SEQ ID NOs: 723, 725, 727 and 729.

Described herein is a base editor protein, wherein the base editor protein comprises a sequence selected from the group consisting of SEQ ID NOs: 724, 726, 728, and 730.

Described herein is a pharmaceutical composition for a human subject comprising: (a) a mRNA encoding a base editor protein, wherein the base editor protein comprises a nucleic acid binding domain, (b) a guide RNA that serves to guide the nucleic acid binding domain to a protospacer sequence on a target gene, and (c) a LNP comprising an amino lipid, a PEG lipid, a phospholipid and a sterol, wherein a total amount of the guide RNA and the mRNA is about 0.01 mg/kg to about 3 mg/kg. In some embodiments, the total amount of the guide RNA and the mRNA is about 0.1 mg/kg to about 3 mg/kg. In some embodiments, the total amount of the guide RNA and the mRNA is about 0.01 mg/kg to about 2 mg/kg. In some embodiments, the total amount of the guide RNA and the mRNA is about 0.1 mg/kg to about 2 mg/kg. In some embodiments, the total amount of the guide RNA and the mRNA is about 0.01 mg/kg to about 1.5 mg/kg. In some embodiments, the total amount of the guide RNA and the mRNA is about 0.1 mg/kg to about 1.5 mg/kg. In some embodiments, the total amount of the guide RNA and the mRNA is about 0.01 mg/kg to about 1.25 mg/kg. In some embodiments, the total amount of the guide RNA and the mRNA is about 0.1 mg/kg to about 1.25 mg/kg. In some embodiments, the total amount of the guide RNA and the mRNA is about 0.01 mg/kg to about 1 mg/kg. In some embodiments, the total amount of the guide RNA and the mRNA is about 0.1 mg/kg to about 1 mg/kg. In some embodiments, the total amount of the guide RNA and the mRNA is about 0.1 mg/kg. In some embodiments, the total amount of the guide RNA and the mRNA is about 0.2 mg/kg. In some embodiments, the total amount of the guide RNA and the mRNA is about 0.3 mg/kg. In some embodiments, the total amount of the guide RNA and the mRNA is about 0.4 mg/kg. In some embodiments, the total amount of the guide RNA and the mRNA is about 0.5 mg/kg. In some embodiments, the total amount of the guide RNA and the mRNA is about 0.6 mg/kg. In some embodiments, the total amount of the guide RNA and the mRNA is about 0.7 mg/kg. In some embodiments, the total amount of the guide RNA and the mRNA is about 0.8 mg/kg. In some embodiments, the total amount of the guide RNA and the mRNA is about 0.9 mg/kg. In some embodiments, the total amount of the guide RNA and the mRNA is about 1 mg/kg. In some embodiments, the total amount of the guide RNA and the mRNA is about 1 mg/kg to about 3 mg/kg. In some embodiments, the total amount of the guide RNA and the mRNA is about 1.1 mg/kg to about 3 mg/kg. In some embodiments, the total amount of the guide RNA and the mRNA is about 1.2 mg/kg to about 3 mg/kg. In some embodiments, the total amount of the guide RNA and the mRNA is about 1.3 mg/kg to about 3 mg/kg. In some embodiments, the total amount of the guide RNA and the mRNA is about 1.4 mg/kg to about 3 mg/kg. In some embodiments, the total amount of the guide RNA and the mRNA is about 1.5 mg/kg to about 3 mg/kg. In some embodiments, the total amount of the guide RNA and the mRNA is about 1.6 mg/kg to about 3 mg/kg. In some embodiments, the total amount of the guide RNA and the mRNA is about 1.7 mg/kg to about 3 mg/kg. In some embodiments, the total amount of the guide RNA and the mRNA is about 1.8 mg/kg to about 3 mg/kg. In some embodiments, the total amount of the guide RNA and the mRNA is about 1.9 mg/kg to about 3 mg/kg.

In some embodiments, the phospholipid is distearoylphosphatidylcholine (DSPC). In some embodiments, the sterol is cholesterol. In some embodiments, the LNP comprises a N-acetylgalactosamine (GalNAc) lipid receptor targeting conjugate.

Described herein is a method for treating or preventing an atherosclerotic cardiovascular disease in a human subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of pharmaceutical composition of any one of claims 116 - 219 .

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference in their entireties to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

Novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:

FIG. 1 presents data from an in vitro potency study illustrating the percent editing of PCSK9 gene in primary human hepatocytes (PHH) as comparted to primary non-human primate hepatocytes (e.g., primary cyno hepatocytes (PCH)) using an LNP PCSK9 base editor formulation comprising a payload of mRNA MA004 and guide RNA GA346 at 1:1 mRNA:gRNA weight ratio and titrated at different concentrations against multiple lots of PHH and PCH cells. As illustrated in FIG. 1 , the administered PCSK9 base editor formulation appears more potent in human than non-human primate hepatocytes.

FIG. 2 illustrates a study protocol using LNP PCSK9 base editor formulation comprising a payload of mRNA MA004 and guide RNA GA346 at 1:1 mRNA:gRNA weight ratio involving a first group of 4 NHPs intravenously infused with a single dose of 0.75 mg/kg, a second group of 22 NHPs intravenously infused with a single dose of 1.5 mg/kg, and third group (âvehicle controlâ) of 10 NHPs intravenously infused with a single dose of the same LNP delivery vehicle without the gRNA and mRNA drug substance payload. The dose is measured by the total weight of mRNA and gRNA over the weight of the subject.

FIGS. 3 - 7 is data obtained from the study described in FIG. 2 setting forth PCSK9 editing percent change from baseline through liver biopsy assessing whole liver DNA editing at day 15 post infusion and PCSK9 protein reduction at day 14 post infusion ( FIG. 3 ), PCSK9 protein reduction over an extended period of time post infusion ( FIG. 4 ), LDL-C reduction over an extended period of time post infusion ( FIG. 5 ), ALT enzyme levels over an extended period of time post infusion ( FIG. 6 ), and fasting glucose levels over an extended time period post infusion ( FIG. 7 ).

FIGS. 8 - 10 illustrate a mouse study protocol ( FIG. 8 ) and data generated from the study supporting the durability of liver editing using the PCSK9 base editor LNP formulations described herein in regenerated PCSK9 edited liver cells post intravenous infusion ( FIGS. 9 - 10 ). Each dot in the graphs depicted in FIGS. 8 - 9 represents a mouse.

FIG. 11 illustrates data from an NHP study that shows no evidence of editing in sperm from sexually mature male NHPs post intravenous infusion of PCSK9 base editor LNP formulation described herein.

FIGS. 12 - 15 is a study protocol and data generated therefrom assessing potential off-target candidate sites of PCSK9 base editor formulations described herein. FIG. 12 is a schematic illustrating the experimental methods used for evaluating the presence of actual off-target editing by the PCSK9 base editor formulations described herein. FIG. 13 illustrates the high sensitivity of the validation assay employed. FIGS. 14 - 15 are jitter plots generated from the off-target protocol and the validation assay employed showing that there is no detectable off target editing in primary human liver and spleen cells among the top 244 off target candidate sites identified.

FIG. 16 illustrates data from a bio-distribution study of NHPs intravenously dosed with single 1 mg/kg LNP constituted with an ABE mRNA MA004 and guide RNA GA346. The NHPs were sacrificed on day 15 post infusion and tissue samples taken and analyzed for adenine editing of the PCSK9 gene. PCSK9 editing was observed to be predominately distributed to the liver.

FIG. 17 illustrates the potency of disclosed gRNA variants directed to ANGPTL3 and their on-target editing percentage of ANGPTL3 at position 6 in human primary hepatocytes. It should be understood that the â position 6,â as used in the data referencing position 6, refers to the 6th position counting from the 5â² end of the protospacer sequence (i.e., the opposite end from the PAM). The gRNA variants were transfected into human primary hepatocyte cells together with ABE mRNA MA004 at the concentrations noted therein in a manner described herein.

FIG. 18 illustrates the potency truncated guide RNA GA441 (n-1: GA475, n-2: GA576, n-3: GA477) and their on-target editing percentage of ANGPTL3 at the desired editing position in Human primary hepatocytes combined with the observed corresponding reduction of potential off-target editing at selected off-target candidate sites ( OT # 1, OT # 2, OT # 3, OT #4). The gRNA truncated variants were transfected into human primary hepatocyte cells together with mRNA MA004 in a manner described herein and illustrate how such truncated variants of gRNA GA441 impact potential off-target sites more than on-target editing.

FIG. 19 shows exemplary modified ABE variants transfected with gRNA GA441 and their on-target editing percentage of ANGPTL3 at position 6 in primary human hepatocytes (PHH) transfected with gRNA GA441 together with the identified ABE variant at the noted concentrations in a manner described herein. Each sample was normalized to the respective MA004 ABE mRNA sample per concentration. Each set of columns in the illustrated graph correspond to MA004, MA040, MA041, MA045, MA064, MA065, MA066, and MA067, in order, as read from left to right as further represented by the hash marks in the legend.

FIGS. 20 A- 20 E show data generated using various ANGPTL3 gRNAs and ABE mRNAs mRNA MA004 and variants thereof. MA040, MA041 and MA045 to illustrate the relative potency of each combination of gRNA and mRNA vis-Ã -vis on-target editing of ANGPTL3 in human primary hepatocytes transfected at the noted concentrations. FIG. 20 A , FIG. 20 B , and FIG. 20 C are results from experiment 1 using MA004 encoding ABE8.8, MA040 encoding ABE8.8 D1135E, and MA041 encoding ABE8.8 R691A/D1135E, respectively, with ANGPTL3 targeted gRNA GA441, GA442, GA472, GA473, GA474, GA475, GA476 and GA477 as specified in the gRNA legend and illustrated in the graphs in order from left to right. FIG. 20 D and FIG. 20 E are results from experiment 2 using MA004 encoding ABE8.8, and MA045 encoding ABE8.8 R691A, respectively.

FIG. 21 is a comparative graph illustrating the percent on target editing of PCSK9 of human primary hepatocytes transfected with the referenced gRNA variants and ABE mRNA MA004 at the noted 4 concentrations. The graph illustrates the relative potency between different gRNAs in human primary hepatocytes. From left to right of the graph, the gRNA variants in the 4 concentrations are GA346, GA376, GA377, GA380, GA381, GA382, GA383, GA384, GA385, GA386, GA387, GA388, GA389, and GA391 respectively.

FIG. 22 is a comparative graph illustrating the percent on target editing of PCSK9 of cyno primary hepatocytes transfected with the referenced gRNA variants and ABE mRNA MA004 at the noted 4 concentrations. The graph illustrates the relative potency in primary hepatocytes between spacer and tracr chemistries variants of gRNA GA346 embodied in the referenced gRNA variants. From left to right of the graph, the gRNA variants in the 4 concentrations are GA346, GA376, GA377, GA380, GA381, GA382, GA383, GA384, GA385, GA386, GA387, GA388, GA389, and GA391 respectively.

FIG. 23 is a comparative graph illustrating the percent on-target editing of PCSK9 of primary hepatocyte transfected with ABE mRNA M004 in combination with gRNAs GA376, GA377, GA380-GA389, GA391 and GA066 (from left to right) between guide concentration of 312.5 ng/TA/mL to 2500 ng/TA/mL. Four different lots of GA066 were used in this study. GA376, GA377, GA380, GA383, GA385 and GA386 showed comparable dose response to GA066. The graph illustrates the relative potency between the gRNAs in human primary hepatocytes.

FIG. 24 is a table illustrating predicted exposures for LNP constituted with an ABE mRNA MA004 and guide RNA GA346 in Humans. Pharmacokinetic (âPKâ) modeling using the NHP data disclosed herein was used to predict exposure correlations in human subjects and potential safety margin. Abbreviations: AUC=area under the plasma concentration-time curve; plasma C max =plasma maximal concentration; NHP=non-human primate. The modeling employed the following assumption:

(a) A graded infusion: the first 15 minutes the infusion rate (in terms of volume) is 1 mL/min; for the remaining infusion duration, the infusion rate is 3 mL/min. (b) Predicted exposure for a 75 kg person. (c) For NHP, 2 mg/kg (single dosing plasma Cmax and AUC inf were the mean values.

FIG. 25 is a table showing the percent reduction in PCSK9 human subjects at different doses of an ABE mRNA MA004 and guide RNA 346 formulated in an LNP described herein based on predictive PK-PD modeling and broken out by human subject body weight and equivalent and 3-fold higher potency in humans than NHPs. PCSK9% reduction=100%âPCSK9% remaining relative to baseline. This is just one method of predicting the human dosing and other factors might affect the particular mRNA used and the assay implemented.

FIG. 26 shows relative editing percentage of an off-target candidate site B2 in primary human hepatocytes transfected with the referenced ABE mRNA and the noted ANGPTL3 guide RNAs GA441, GA475 and GA476. The relative editing percentage of each sample was normalized to the GA441/MA004 sample for site B2.

FIG. 27 shows relative editing percentage of an off-target candidate site B6 in primary human hepatocytes transfected with the referenced ABE mRNA and the noted ANGPTL3 guide RNAs GA441, GA475 and GA476. The relative editing percentage of each sample was normalized to the GA441/MA004 sample for site B6.

FIG. 28 A illustrates an exemplary scheme of the gene editing system comprising a guide nucleic acid. The guide nucleic acid comprises a spacer sequence with a first exemplary motif gRNAs GA837, GA693 and GA749 disclosed herein are embodiments of this motif.

FIG. 28 B illustrates another exemplary scheme of the gene editing system comprising a guide nucleic acid. The guide nucleic acid comprises a spacer sequence with a second exemplary motif gRNAs GA745, GA692 and GA748 disclosed herein are embodiments of this motif.

FIG. 28 C illustrates another exemplary scheme of the gene editing system comprising a guide nucleic acid. The guide nucleic acid comprises a spacer sequence with a third exemplary motif gRNAs GA682, GA723 and GA746 disclosed herein are embodiments of this motif.

FIG. 28 D illustrates another exemplary scheme of the gene editing system comprising a guide nucleic acid. The guide nucleic acid comprises a spacer sequence with a fourth exemplary motif gRNAs GA691, GA724 and GA747 disclosed herein are embodiments of this motif.

FIG. 29 shows the percent on target editing of the target gene ANGPTL3 results from the initial on-target in vitro screening for the guide nucleic acids comprising the spacer sequences (guide nucleic

CLAIMS

Claims ( 25 )

1 .- 219 . (canceled)

220 . A hybrid guide nucleic acid, wherein the hybrid guide nucleic acid comprises (i) a spacer sequence comprising a deoxyribonucleotide and a ribonucleotide comprising a ribose, wherein a 2â² hydroxyl group of the ribose is covalently linked to a methyl group (2â²-OMe), and (ii) a binding scaffold.

221 . The hybrid guide nucleic acid of claim 220 , wherein the spacer sequence comprises an unmodified ribonucleotide.

222 . The hybrid guide nucleic acid of claim 220 , wherein the deoxyribonucleotide is located on position 3, 4, 6, 7 or 8 from the 5â² end of the spacer sequence.

223 . The hybrid guide nucleic acid of claim 220 , wherein the spacer sequence comprises deoxyribonucleotides on positions

3, 4, 6 and 7, 3 and 4, 6 and 7, or 3, 4, 6, 7 and 8, from the 5â² end of the spacer sequence.

224 . The hybrid guide nucleic acid of claim 220 , wherein the spacer sequence comprises one to ten deoxyribonucleotides.

225 . The hybrid guide nucleic acid of claim 220 , wherein the spacer sequence comprises a phosphorothioate backbone modification (PS).

226 . The hybrid guide nucleic acid of claim 220 , wherein the spacer sequence comprises a (2â²-OMe)PS(2â²-OMe)PS(DNA)PS(DNA)(RNA)(DNA)(DNA) motif, optionally wherein the (2â²-OMe)PS(2â²-OMe)PS(DNA)PS(DNA)(RNA)(DNA)(DNA) motif is located at the 5â² end of the spacer sequence.

227 . The hybrid guide nucleic acid of claim 2206 , wherein the spacer sequence comprises a sequence with at least about 80%, about 90%, about 95%, about 99%, about 99.5%, or about 100% sequence identity or sequence similarity to SEQ ID NO: 28 or 29.

228 . The hybrid guide nucleic acid of claim 220 , wherein the spacer sequence comprises a (2â²-OMe)PS(2â²-OMe)PS(DNA)PS(DNA)(RNA)(DNA)(DNA)(DNA) motif, optionally wherein the (2â²-OMe)PS(2â²-OMe)PS(DNA)PS(DNA)(RNA)(DNA)(DNA)(DNA) motif is located at the 5â² end of the spacer sequence.

229 . The hybrid guide nucleic acid of claim 220 , wherein the spacer sequence comprises a sequence with at least about 80%, about 90%, about 95%, about 99%, about 99.5%, or about 100% sequence identity or sequence similarity to SEQ ID NO: 30 or 31.

230 . The hybrid guide nucleic acid of claim 220 , wherein the spacer sequence comprises a (2â²-OMe)PS(2â²-OMe)PS(DNA)PS(DNA)(DNA)(DNA)(DNA) motif, optionally wherein the (2â²-OMe)PS(2â²-OMe)PS(DNA)PS(DNA)(DNA)(DNA)(DNA) motif is located at the 5â² end of the spacer sequence.

231 . The hybrid guide nucleic acid of claim 220 , wherein the spacer sequence comprises a sequence with at least about 80%, about 90%, about 95%, about 99%, about 99.5%, or about 100% sequence identity or sequence similarity to SEQ ID NO: 11 or 12.

232 . The hybrid guide nucleic acid of claim 220 , wherein the spacer sequence corresponds to a protospacer on a target gene, and wherein the target gene is ANGPTL3.

233 . The hybrid guide nucleic acid of claim 220 , wherein the hybrid guide nucleic acid comprises a sequence with at least about 80%, about 90%, about 95%, about 99%, about 99.5%, or about 100% sequence identity or sequence similarity to a sequence selected from the group consisting of SEQ ID NOs: 79-82 and 106-113.

234 . An in vivo hybrid guide gene editing system comprising:

(a) the hybrid guide nucleic acid of claim 220 , and (b) a gene editor protein or a component thereof comprising a nucleic acid binding domain, or a nucleic acid encoding the gene editor protein or the component thereof.

235 . The in vivo hybrid guide gene editing system of claim 234 , wherein the gene editor protein or the component thereof further comprises a deaminase.

236 . The in vivo hybrid guide gene editing system of claim 234 , wherein the nucleic acid binding domain is capable of binding to DNA or RNA.

237 . The in vivo hybrid guide gene editing system of claim 234 , wherein the nucleic acid binding domain comprises a CRISPR protein or a fragment thereof, a catalytically impaired nuclease, or a prime editing protein or a fragment thereof.

238 . The in vivo hybrid guide gene editing system of claim 234 , wherein the gene editor protein or the component thereof comprises a single fusion protein or two or more proteins.

239 . The in vivo hybrid guide gene editing system of claim 234 , wherein the nucleic acid encoding the gene editor protein or the component thereof is an mRNA.

240 . The in vivo hybrid guide gene editing system of claim 234 , wherein the gene editor protein or the component thereof affects less than about 10%, about 9%, about 8%, about 7%, about 6%, about 5%, about 4%, about 3%, about 2%, or about 1% editing on all off-target sites as compared to a gene editing system comprising a corresponding guide nucleic acid without the deoxyribonucleotide.

241 . The in vivo hybrid guide gene editing system of claim 234 , wherein the gene editor protein or the component thereof affects over about 50%, about 60%, about 70%, about 80%, about 90%, or about 95% editing on the target gene as compared to a gene editing system comprising a corresponding guide nucleic acid without the deoxyribonucleotide.

242 . A pharmaceutical composition comprising the hybrid guide nucleic acid of claim 220 or the in vivo hybrid guide gene editing system of claim 234 .

243 . A method for treating or preventing an atherosclerotic cardiovascular disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the hybrid guide nucleic acid of claim 220 , the in vivo hybrid guide gene editing system of claim 234 , or the pharmaceutical composition of claim 242 .

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