Antisense compounds and uses thereof
AssigneesIonis Pharmaceuticals, Inc., Cold Spring Harbor Laboratory
InventorsFrank Rigo, C. Frank Bennett, Adrian R. Krainer, Zhenxun Wang
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Abstract
The present invention provides compounds comprising oligonucleotides complementary to a pyruvate kinase M transcript. Certain such compounds are useful for hybridizing to a pyruvate kinase M transcript, including but not limited to a pyruvate kinase M transcript in a cell. In certain embodiments, such hybridization results in modulation of splicing of the pyruvate kinase M transcript. In certain embodiments, such compounds are used to treat one or more symptoms associated with cancer.
Claims20
A method of modulating splicing of a PK-M pre-mRNA transcript in a cell comprising contacting the cell with an antisense compound comprising a single-stranded modified oligonucleotide, wherein the single-stranded modified oligonucleotide consists of 15 to 25 linked nucleosides and has a nucleobase sequence comprising a complementary region, wherein the complementary region comprises at least 15 contiguous nucleobases and is 100% complementary to an equal-length portion of a target region of a PK-M transcript, wherein the target region of the PK-M transcript is within nucleobase 29153 and nucleobase 29281 of SEQ ID NO:
- 1, wherein each nucleoside of the single-stranded modified oligonucleotide comprises a modified sugar moiety, wherein the single-stranded modified oligonucleotide comprises 2′-deoxyribose unmodified sugar moieties, wherein the single-stranded modified oligonucleotide does not comprise more than 4 contiguous unmodified 2′-deoxynucleosides, and wherein inclusion of exon 9 of the PK-M transcript is increased and exclusion of exon 10 of the PK-M transcript is increased following contacting the cell with the antisense compound.
A method of modulating splicing of a PK-M pre-mRNA transcript in a cell comprising contacting the cell with an antisense compound comprising a single-stranded modified oligonucleotide, wherein the single-stranded modified oligonucleotide consists of 15 to 25 linked nucleosides and has a nucleobase sequence comprising a complementary region, wherein the complementary region comprises at least 15 contiguous nucleobases and is 100% complementary to an equal-length portion of a target region of a PK-M transcript, wherein the target region of the PK-M transcript is within nucleobase 29153 and nucleobase 29281 of SEQ ID NO:
- 1, wherein the single-stranded modified oligonucleotide comprises a sugar motif of kddkddkddkddk or kkddkddkddkddk, each “k” represents a cEt bicyclic modified sugar moiety and each “d” represents a 2′-deoxyribose unmodified sugar moiety, wherein the single-stranded modified oligonucleotide does not comprise more than 4 contiguous unmodified 2′-deoxynucleosides, and wherein inclusion of exon 9 of the PK-M transcript is increased and exclusion of exon 10 of the PK-M transcript is increased following contacting the cell with the antisense compound.
Dependencies are inferred from the claim text.