Manufacture of antisense oligomers and conjugates targeting PCSK9
AssigneeRoche Innovation Center Copenhagen A/S
InventorsNanna Albæk, Maj Hedtjärn, Marie Wickstrom Lindholm, Niels Fisker Nielsen, Andreas Petri, Jacob Ravn
Life of this patent
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Abstract
The present invention relates to oligomeric compounds and conjugates thereof that target Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) PCSK9 mRNA in a cell, leading to reduced expression of PCSK9. Reduction of PCSK9 expression is beneficial for a range of medical disorders, such as hypercholesterolemia and related disorders.
Claims45
A method of manufacturing a compound consisting of an antisense oligomer that is 16 contiguous nucleotides in length, the method comprising chemically synthesizing the compound using sequential solid phase oligonucleotide synthesis, wherein the sequence of the antisense oligomer is 100% complementary to the sequence of SEQ ID NO:
- 31, wherein the antisense oligomer is a gapmer comprising at least one LNA unit, and wherein the antisense oligomer targets mRNA encoding PCSK9.
A method of manufacturing an antisense oligonucleotide conjugate comprising covalently attaching at least one non-nucleotide or non-polynucleotide moiety covalently to an antisense oligomer that is 16 contiguous nucleotides in length directly or via a linker positioned between the antisense oligomer sequence and the non-nucleotide or non-polynucleotide moiety, wherein the sequence of the antisense oligomer is 100% complementary to the sequence of SEQ ID NO:
- 31, wherein the antisense oligomer is a gapmer comprising at least one LNA unit, and wherein the antisense oligonucleotide conjugate targets mRNA encoding PCSK9.
A method of manufacturing an antisense oligonucleotide conjugate of SEQ ID NO:
- 18
- wherein
- a superscript L identifies a beta-D-oxy LNA unit,
- a MeC identifies a 5-methylcytosine unit,
- a subscript s identifies a phosphorothioate internucleoside linkage,
- and wherein
- is a Conj 2a asialoglycoprotein receptor targeting conjugate moiety
- and wherein the antisense oligonucleotide conjugate targets mRNA encoding PCSK9, the method comprising covalently attaching the Conj 2a asialoglycoprotein receptor targeting conjugate moiety to the 5′ end of an antisense oligomer of SEQ ID NO:
- 2.
A method of manufacturing an antisense oligonucleotide conjugate of SEQ ID NO:
- 19
- wherein
- a superscript L identifies a beta-D-oxy LNA unit,
- a MeC identifies a 5-methylcytosine unit,
- a subscript s identifies a phosphorothioate internucleoside linkage,
- and wherein
- is a Conj 2a asialoglycoprotein receptor targeting conjugate moiety
- and wherein the antisense oligonucleotide conjugate targets mRNA encoding PCSK9, the method comprising covalently attaching the Conj 2a asialoglycoprotein receptor targeting conjugate moiety to the 5′ end of an antisense oligomer of SEQ ID NO:
- 3.
Dependencies are inferred from the claim text.