Prekallikrein-modulating compositions and methods of use thereof
AssigneeADARx Pharmaceuticals, Inc.
InventorsZhen Li, Rui Zhu, Zhiqing (Joel) Zhou, Kimberly Fultz, Sean Studer
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Abstract
Aspects of the disclosure provide compounds, compositions, and methods for modulating the expression or activity of plasma prekallikrein (PKK). In some aspects, the compounds, compositions, and methods of the disclosure can be used to reduce the expression of PKK mRNA in a cell or animal. In some aspects, the compounds, compositions, and methods of the disclosure can be used to reduce the expression of PKK protein in a cell or animal.
Claims36
A compound comprising a first modified oligonucleotide 14 to 23 linked nucleosides in length having a nucleobase sequence comprising at least 14 contiguous nucleobases of the nucleobase sequence of SEQ ID NO:
- 619 and a second modified oligonucleotide having a region of complementarity to the first modified oligonucleotide, wherein one or more GalNAc are attached to the 2′ or 3′ position of the ribosyl ring of the 5′ nucleoside of the first modified oligonucleotide, wherein the second modified oligonucleotide consists of the formula:
- mU*fG*mU.fA.mA.fU.mU.fC.mA.fA.mA.fG.mG.fA.mG.fC.mC.fU.mG.fG.mA*mG*mU (SEQ ID NO:
- 312),
- wherein:
- ‘A’ is a nucleoside having an adenine nucleobase, ‘G’ is a nucleoside having a guanine nucleobase, ‘C’ is a nucleoside having a cytosine nucleobase, and ‘11’ is a nucleoside having a uracil nucleobase;
- ‘m’ is a 2′-O-methyl sugar modification;
- ‘f’ is a 2′-F sugar modification;
- ‘*’ is a phosphorothioate internucleoside linkage;
- and
- ‘.’ is a phosphate internucleoside linkage.
A compound comprising a first modified oligonucleotide and a second modified oligonucleotide 14 to 23 linked nucleosides in length having a region of complementarity to the first modified oligonucleotide, wherein the first modified oligonucleotide consists of the formula:
- H9*mU*mC.mC.mA.mG.mG.fC.mU.fC.fC.fU.fU.mU.mG.mA.mA.mU.mU.mA.mC*mA*dQ (SEQ ID NO:
- 619),
- wherein:
- ‘A’ is a nucleoside having an adenine nucleobase, ‘G’ is a nucleoside having a guanine nucleobase, ‘C’ is a nucleoside having a cytosine nucleobase, and ‘11’ is a nucleoside having a uracil nucleobase;
- ‘m’ is a 2′-O-methyl sugar modification;
- ‘f’ is a 2′-F sugar modification;
- ‘*’ is a phosphorothioate internucleoside linkage;
- ‘.’ is a phosphate internucleoside linkage;
- ‘dQ’ is an inverted abasic deoxyribose;
- and
- ‘H9’ is of the formula:
Dependencies are inferred from the claim text.