US2023414649A1PendingUtilityA1
Antisense oligonucleotides and uses thereof
Assignee: FUND CENTRE DE REGULACIO GENÒMMICAPriority: Mar 19, 2018Filed: Apr 18, 2023Published: Dec 28, 2023
Est. expiryMar 19, 2038(~11.6 yrs left)· nominal 20-yr term from priority
Inventors:Jordi Hernández RiberaJuan Alberto Valcárcel JuárezElias BecharaManuel Serrano MaruganMiguel Rovira Del OlmoPablo José Fernández Marcos
A61K 31/712A61P 35/00A61K 9/0019A61K 31/7125C12N 15/113C12N 2310/11C12N 2310/315C12N 2310/321C12N 2320/33
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Claims
Abstract
Disclosed herein are novel compounds comprising antisense oligonucleotides that regulate the splicing of NUMB. In particular, an antisense oligonucleotide for reducing inclusion of NUMB exon 9 in a population of mature NUMB transcripts is provided. The antisense oligonucleotide comprises a sequence of at least 7 nucleotides that is complementary to a target region within exon 9 of a NUMB transcript. Pharmaceutical compositions comprising the antisense oligonucleotide and methods of treating a proliferative disease using the compounds or compositions of the invention are also described.
Claims
exact text as granted — not AI-modified1 - 15 . (canceled)
16 . An antisense oligonucleotide for reducing inclusion of NUMB exon 9 in a population of mature NUMB transcripts, the antisense oligonucleotide comprising a sequence of at least 7 nucleotides that is complementary to a target region of a NUMB transcript within exon 9 comprising SEQ ID NO: 2 or a homologue thereof.
17 . The antisense oligonucleotide of claim 16 , wherein the target region is comprised within the sequence CUAAUGGCACUGACUCAGCCUUCCAUGUGCUUGCUAAGCCAGCCCAUACU (SEQ ID NO: 305), CCGUAGCAAUGCCUGUGCGUGAAACCAACCCUUGGGCCCAUG (SEQ ID NO: 10), or CCCCUGAUGCUGCUAACAAGGAAAUUGCAGCCACAUGUUCGG (SEQ ID NO: 11), or a homologue thereof.
18 . The antisense oligonucleotide of claim 16 , wherein the target region is comprised within the sequence CUAAUGGCACUGACUCAGCCUUCCAUGUGCUUGCUAAGC (SEQ ID NO: 9), CUAAUGGCACUGACUCAGCCU (SEQ. ID NO: 44), CCUGUGCGUGAAACCAACCCU (SEQ ID NO: 31), GCUAACAAGGAAAUUGCAGCC (SEQ ID NO: 32) or UGGGCCCAUGCCCCUGAUGCU (SEQ ID NO: 35), or a homologue thereof.
19 . The antisense oligonucleotide of claim 16 , consisting essentially of a nucleotide sequence complementary to a contiguous nucleotide sequence of a NUMB transcript.
20 . The antisense oligonucleotide of claim 16 , wherein the antisense oligonucleotide comprises a nucleotide sequence that is complementary to a target region comprising between 7 and 25 nucleotides of NUMB exon 9; or is complementary to a target region of at least 13 nucleotides of NUMB exon 9.
21 . The antisense oligonucleotide of claim 16 , wherein the oligonucleotide is between 7 and 31 nucleotides long.
22 . The antisense oligonucleotide of claim 16 , wherein the oligonucleotide does not comprise a sequence that is complementary to the 5′ and/or 3′ exon-intron junction of exon 9.
23 . The antisense oligonucleotide of claim 16 , wherein the oligonucleotide is an RNA or a modified RNA molecule, a DNA or a modified DNA molecule, or a mixture of native or modified RNA and native or modified RNA.
24 . The antisense oligonucleotide of claim 23 , wherein the modified RNA or DNA molecule comprises one or more chemical modifications selected from the group consisting of: a locked nucleic acid, a phosphorothioate linkage, a 2′-O-methylated nucleotide, a 2′-O-methoxyethyl modified (2′MOE) nucleotide, methylated cytosine, a constrained ethyl (cET) nucleic acid, a bridged nucleic acid (BNA), a phosphorodiamidate morpholino oligomer (PMO), a peptide nucleic acid (PNA), a cyclohexene nucleic acid (CeNA), a tricycle-DNA (tcDNA), N3′-P5′ phosphoroamidate (NP), 2′-fluoro-2′-deoxyadenosine-5′-triphosphate, 2′-fluoro-2′-deoxycytidine-5′-triphosphate, 2′-fluoro-2′-deoxyguanosine-5′-triphosphate, 2′-fluoro-2′-deoxyuridine-5′-triphosphate, 2′-fluoro-2′-deoxythymidine-5′-triphosphate, methyladenosine-5′-triphosphate, 2′-O-methylcytidine-5′-triphosphate, 2′-O-methylguanosine-5′-triphosphate, 2′-O-methyluridine-5′-triphosphate, 2′-O-methylinosine-5′-triphosphate, 2′-O-methyl-2-2′-O-methyl-5-2′-O-2′-O-methylpseudouridine-5′-triphosphate, and methyluridine-5′-triphosphate.
25 . The antisense oligonucleotide of claim 16 , which is between 7 and 31 nucleotides long, and wherein the oligonucleotide is a locked nucleic acid.
26 . The antisense oligonucleotide of claim 16 , which is between 7 and 31 nucleotides long and wherein the oligonucleotide is a 2′-O-methyl phosphorothioate ribonucleic acid; or which is between 7 and 31 nucleotides long and wherein the oligonucleotide is a 2′-O-methoxyethyl-modified phosphorothioate ribonucleic acid.
27 . The antisense oligonucleotide of claim 26 , which is between 18 and 25 nucleotides long, and wherein the oligonucleotide is a 2′-O-methyl phosphorothioate ribonucleic acid.
28 . The antisense oligonucleotide of claim 26 , wherein all of the nucleotides of the antisense oligonucleotide are 2′-O-methylated nucleotides.
29 . The antisense oligonucleotide of claim 26 , which is between 18 and 25 nucleotides long, and wherein the oligonucleotide is a 2′-O-methoxyethyl-modified phosphorothioate ribonucleic acid.
30 . The antisense oligonucleotide of claim 26 , wherein all of the nucleotides of the antisense oligonucleotide are 2′-O-methoxyethylated nucleotides.
31 . The oligonucleotide of claim 16 , wherein at least one cytosine residue within the oligonucleotide is methylated.
32 . The antisense oligonucleotide of claim 16 , wherein the oligonucleotide comprises a sequence selected from:
(a)
(SEQ ID NO: 36)
AGGCUGA,
(SEQ ID NO: 37)
GUCAGUG,
(SEQ ID NO: 38)
CCAUUAG,
(SEQ ID NO: 39)
CUGAGUC,
or
(SEQ ID NO: 40)
AGUGCCA;
and/or
(b)
(SEQ ID NO: 41)
AGGCUGAGUCAGUG,
or
(SEQ ID NO: 42)
GUCAGUGCCAUUAG;
and/or
(c)
(SEQ ID NO: 43)
AGGCUGAGUCAGUGCCAUUAG
or
(SEQ ID NO: 12)
AGGCUGAGUCAGUGCCAUUAG;
and/or
(d)
(SEQ ID NO: 22)
AGGGUUGGUUUCACGCACAGG
or
(SEQ ID NO: 24)
GGCUGCAAUUUCCUUGUUAGC;
and/or
(e)
(SEQ ID NO: 19)
CACAUGGAAGGCUGAGUCAGU;
(SEQ ID NO: 13)
GCUUAGCAAGCACAUGGAAGG;
and
(SEQ ID NO: 20)
AGUAUGGGCUGGCUUAGCAAG
33 . An antisense oligonucleotide for reducing inclusion of NUMB exon 9 in a population of mature NUMB transcripts according to claim 16 , the antisense oligonucleotide comprising a sequence of 19 nucleotides that is complementary to a target region of a NUMB transcript; wherein the target region is comprised within:
the sequence
(SEQ ID NO: 10)
CCGUAGCAAUGCCUGUGCGUGAAACCAA
CCCUUGGGCCCAUG;
or
the sequence
(SEQ. ID NO: 44)
CUAAUGGCACUGACUCAGCCU;
or
the sequence
(SEQ ID NO: 31)
CCUGUGCGUGAAACCAACCCU;
or
the sequence
(SEQ ID NO: 32)
GCUAACAAGGAAAUUGCAGCC;
or
the sequence
(SEQ ID NO: 5)
CCGUAGCAAUGCCUGUGCGUG;
or
the sequence
(SEQ ID NO: 6)
AAACCAACCCUUGGGCCCAUG;
or
the sequence
(SEQ ID NO: 35)
UGGGCCCAUGCCCCUGAUGCU
34 . An antisense oligonucleotide for reducing inclusion of NUMB exon 9 in a population of mature NUMB transcripts according to claim 16 , the antisense oligonucleotide comprising a sequence of 20 nucleotides that is complementary to a target region of a NUMB transcript; wherein the target region is comprised within:
the sequence
(SEQ ID NO: 10)
CCGUAGCAAUGCCUGUGCGUGAAACCAACCCUUGGGCCCAUG;
or
the sequence
(SEQ. ID NO: 44)
CUAAUGGCACUGACUCAGCCU;
or
the sequence
(SEQ ID NO: 31)
CCUGUGCGUGAAACCAACCCU;
or
the sequence
(SEQ ID NO: 32)
GCUAACAAGGAAAUUGCAGCC;
or
the sequence
(SEQ ID NO: 5)
CCGUAGCAAUGCCUGUGCGUG;
or
the sequence
(SEQ ID NO: 6)
AAACCAACCCUUGGGCCCAUG;
or
the sequence
(SEQ ID NO: 35)
UGGGCCCAUGCCCCUGAUGCU;
or
the sequence
(SEQ ID NO: 305)
CUAAUGGCACUGACUCAGCCUUCCAUGUGCUUGCU
AAGCCAGCCCAUACU;
or
the sequence
(SEQ ID NO: 9)
CUAAUGGCACUGACUCAGCCUUCCAUGUGCUUGCUAAGC.
35 . An antisense oligonucleotide for reducing inclusion of NUMB exon 9 in a population of mature NUMB transcripts according to claim 16 , the antisense oligonucleotide comprising a sequence of at least 21 nucleotides that is complementary to a target region of a NUMB transcript; wherein the target region is comprised within:
the sequence
(SEQ ID NO: 10)
CCGUAGCAAUGCCUGUGCGUGAAACCAACCCUUGGGCCCAUG;
or
the sequence
(SEQ. ID NO: 44)
CUAAUGGCACUGACUCAGCCU;
or
the sequence
(SEQ ID NO: 31)
CCUGUGCGUGAAACCAACCCU;
or
the sequence
(SEQ ID NO: 32)
GCUAACAAGGAAAUUGCAGCC;
or
the sequence
(SEQ ID NO: 5)
CCGUAGCAAUGCCUGUGCGUG;
or
the sequence
(SEQ ID NO: 6)
AAACCAACCCUUGGGCCCAUG;
or
the sequence
(SEQ ID NO: 35)
UGGGCCCAUGCCCCUGAUGCU;
or
the sequence
(SEQ ID NO: 305)
CUAAUGGCACUGACUCAGCCUUCCAUGU
GCUUGCUAAGCCAGCCCAUACU;
or
the sequence
(SEQ ID NO: 9)
CUAAUGGCACUGACUCAGCCUUCCAUGUGCUUGCUAAGC.
36 . A pharmaceutical composition comprising:
one or more antisense oligonucleotides according to claim 16 ; and one or more pharmaceutically-acceptable excipients.Join the waitlist — get patent alerts
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