Methods and means for efficient skipping of at least one of the exons 51-53, 55, 57 and 59 of the human duchenne muscular dystrophy gene
The invention relates to a method where a molecule is used for inducing and/or promoting the skipping of at least one of the exons 51-53, 55, 57 and 59 of the DMD pre-mRNA in a patient, preferably in an isolated cell of a patient. The method comprising providing the cell and/or the patient with a molecule. The invention also relates to the molecule and its composition that is being used for inducing exon skipping.
1. An isolated antisense oligonucleotide whose base sequence consists of the base sequence 5′-GGUAAUGAGUUCUUCCAACUGG-3′ (SEQ ID NO: 287), said oligonucleotide comprising a modification.
2. The oligonucleotide of claim 1 , wherein the modified-oligonucleotide comprises at least one nucleotide analogue, wherein the nucleotide analogue comprises a modified base and/or, a modified sugar moiety and/or a modified internucleoside linkage.
3. The oligonucleotide of claim 1 , wherein the modified oligonucleotide comprises a modified internucleoside linkage.
4. The oligonucleotide of claim 2 , wherein all the sugar moieties are modified.
5. The oligonucleotide of claim 2 , wherein all the internucleoside linkages are modified.
6. The oligonucleotide of claim 2 or 4 , wherein the modified sugar moiety is mono- or di-substituted at the 2′, 3′ and/or 5′ position.
7. The oligonucleotide of claim 6 , wherein the modified sugar moiety is a 2′-O-methyl ribose.
8. The oligonucleotide of claim 3 , wherein the modified backbone is a morpholino backbone.
9. The oligonucleotide of claim 2 or 4 , comprising a 2′-O-substituted phosphorothioate moiety.
10. The oligonucleotide of claim 3 or 5 , wherein the modified internucleoside linkage is a phosphorothioate linkage.
11. The oligonucleotide of claim 1 , wherein all sugar moieties are 2′-O-methyl substituted ribose moieties and all internucleoside linkages are phosphorothioate moieties.
12. The oligonucleotide according to claim 3 , comprising: a morpholino backbone, a carbamate backbone, a siloxane backbone, a sulfide backbone, a sulfoxide backbone, a sulfone backbone, a formacetyl backbone, a thioformacetyl backbone, a methyleneformacetyl backbone, a riboacetyl backbone, an alkene containing backbone, a sulfamate backbone, a sulfonate backbone, a sulfonamide backbone, a methyleneimino backbone, a methylenehydrazino backbone and/or an amide backbone.
13. The oligonucleotide of claim 3 , wherein the oligonucleotide comprises a morpholine ring and/or a phosphorodiamidate internucleoside linkage and/or a peptide nucleic acid, and/or a locked nucleic acid.
14. The oligonucleotide of claim 1 , comprising a phosphorothioate internucleoside linkage, and wherein a sugar moiety is 2′-O-methyl substituted.
15. The oligonucleotide of claim 1 , which is a phosphorodiamidate morpholino oligomer (PMO).
16. The oligonucleotide of claim 2 , wherein said oligonucleotide comprises a modified base.
17. The oligonucleotide of claim 1 , said oligonucleotide comprising a locked nucleic acid (LNA).