Chimeric oligomeric compounds for modulation of splicing
View Patent ↗Disclosed herein are compounds, compositions and methods for modulating splicing of a selected target mRNA. Further provided are uses of the disclosed compounds and compositions in the manufacture of a medicament for treatment of diseases and disorders. Methods of enhancing cellular uptake, modulating tissue distribution and enhancing pharmacological activity of RNase H-independent antisense oligonucleotides are also provided.
1. A chimeric RNase H-independent antisense compound 13 to 80 nucleobases in length targeted to a selected target pre-mRNA, wherein the compound comprises:
a modified sugar moiety at the 5′-most nucleoside;
a modified sugar moiety at the 3′-most nucleoside;
internal nucleosides comprising 2, 3, 4 or 5 separate regions of 2′-deoxyribonucleosides, wherein each region consists of 1, 2, 3 or 4 nucleosides; and
at least one nucleoside with a modified sugar moiety separating each region of 2′-deoxynucleosides,
and wherein the chimeric antisense compound has a motif selected from among: 4-3-1-3-1-3-5, 5-3-1-3-1-3-4, 3-2-2-3-2-3-5, 5-3-2-3-2-2-3, 3-3-2-3-2-3-4, 2-3-1-3-1-3-1-3-3, 4-3-2-3-2-3-3, and 2-3-1-3-1-3-1-3-3.
2. The compound of claim 1 , wherein the sugar modification is selected from the group consisting of 2′-O-methoxyethyl, 2′-fluoro, 2′-dimethylaminooxyethoxy, 2′-dimethylaminoethoxyethoxy, 2′-guanidinium, 2′-O-guanidinium ethyl, 2′-carbamate, 2′-aminooxy, 2′-acetamido and locked nucleic acid.
3. The compound of claim 2 , wherein the sugar modification is 2′-O-methoxyethyl.
4. The compound of claim 2 , wherein the sugar modification is locked nucleic acid.
5. The compound of claim 1 , wherein the chimeric antisense compound has a 4-3-1-3-1-3-5 motif.
6. The compound of claim 1 , wherein the chimeric antisense compound has a 3-2-2-3-2-3-5 motif.