Modulation of exon recognition in pre-mrna by interfering with the secondary rna structure
AssigneeAcademisch Ziekenhuis Leiden
InventorJudith Christina Theodora Van DEUTEKOM
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Abstract
The invention relates to oligonucleotides for inducing skipping of exon 53 of the dystrophin gene. The invention also relates to methods of inducing exon 53 skipping using the oligonucleotides.
Claims21
A method for inducing the skipping of exon 53 of the human dystrophin pre-mRNA in a subject with Duchenne Muscular Dystrophy (DMD) or Becker Muscular Dystrophy (BMD), or a cell derived from the subject, said method comprising providing an oligonucleotide of 15 to 80 nucleotides in length to said subject or said cell, said oligonucleotide comprising a nucleotide sequence which is complementary to a target sequence of exon 53 of the human dystrophin pre-mRNA, wherein said target sequence comprises a nucleotide sequence that is complementary to CUGUUGCCUCCGGUUCUG (SEQ ID NO:
- 29), wherein said oligonucleotide induces skipping of said exon in the subject or the cell and wherein mRNA produced from skipping exon 53 of the dystrophin pre-mRNA encodes a functional dystrophin protein or a dystrophin protein of a Becker subject.
A method for treating Duchenne Muscular Dystrophy (DMD) or Becker Muscular Dystrophy (BMD) in a subject by inducing the skipping of exon 53 of the human dystrophin pre-mRNA, said method comprising providing an oligonucleotide of 15 to 80 nucleotides in length, said oligonucleotide comprising a nucleotide sequence which is complementary to a target sequence of exon 53 of the human dystrophin pre-mRNA, wherein said target sequence comprises a nucleotide sequence that is complementary to CUGUUGCCUCCGGUUCUG (SEQ ID NO:
- 29), and wherein said oligonucleotide induces skipping of said exon in the subject.
An isolated antisense oligonucleotide comprising:
- a) a sequence of 15 to 80 nucleotides comprising at least 15 consecutive nucleotides of CUGUUGCCUCCGGUUCUG (SEQ ID NO:
- 29);
- and
- b) at least one modification selected from the group consisting of 2′-O-methyl, 2′-O-methyl-phosphorothioate, a morpholine ring, a phosphorodiamidate linkage, a peptide nucleic acid and a locked nucleic acid;
- wherein the oligonucleotide specifically hybridizes to an exon 53 target region of human dystrophin DNA or pre-mRNA inducing exon 53 skipping.
An expression vector encoding a transcript comprising an oligonucleotide, wherein the oligonucleotide is 15 to 80 nucleotides in length, said oligonucleotide comprising a nucleotide sequence which is complementary to a target sequence of exon 53 of the human dystrophin pre-mRNA, wherein said target sequence comprises a nucleotide sequence that is complementary to CUGUUGCCUCCGGUUCUG (SEQ ID NO:
- 29).
Dependencies are inferred from the claim text.