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US 9,790,494 B2Granted
Multimeric oligonucleotide compounds having non-nucleotide based cleavable linkers
AssigneeTranslate Bio MA, Inc.
InventorsEugen Uhlmann, Romesh Subramanian, Arthur M. Krieg
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Abstract
The disclosure provides multimeric oligonucleotide compounds, comprising two or more target-specific oligonucleotides (e.g., antisense oligonucleotides (ASOs)), each being resistant to cleavage, and linked together by a cleavable linker. In particular, two or more linked target-specific oligonucleotides, each to a different target, allows concomitant inhibition of multiple genes' expression levels, while exhibiting favorable pharmacokinetic and pharmacodynamic properties. Methods of making and uses of the described compounds are also provided.
Claims20
A compound comprising the general formula:
- X-L-X,
- wherein each X is independently a single-stranded targeting oligonucleotide of 8 to 50 nucleotides in length having a region of complementarity comprising at least 7 contiguous nucleotides complementary to a different target nucleic acid than the other X, wherein each X comprises phosphorothioate internucleotide linkages,
- wherein L is a linker that links the two Xs and that is more susceptible to cleavage in a mammalian extract than each X,
- wherein L comprises a peptide which includes an endopeptidase cleavage site, wherein the endopeptidase is trypsin, chymotrypsin, elastase, thermolysin, pepsin, endopeptidase V8, cathepsin B, cathepsin D, cathepsin L, cathepsin C, papain, cathepsin S or endosomal acidic insulinase, and
- wherein at least one of the different target nucleic acids is an mRNA that encodes a protein having an activity in liver.
2 more elements
Dependencies are inferred from the claim text.