Endosomal cleavable linkers
The present disclosure relates generally to cleavable linkers and uses thereof.
1. A molecule comprising at least two effector molecules, wherein the effector molecules are connected together via an endosomal cleavable linker, wherein the effector molecules are selected independently from the group consisting of siRNA, shRNA, antisense oligonucleotide, microRNA, anti-microRNA or antimir, supermir, antagomir, ribozyme, triplex-forming oligonucleotide, decoy oligonucleotide, splice-switching oligonucleotide, immunostimulatory oligonucleotide, RNA activator, U1 adaptor, and any combinations thereof, and wherein the linker comprises:
and
wherein n and m are integers selected independently from 1-12 inclusive.
2. The molecule of claim 1 , wherein at least one ligand is conjugated with the molecule.
3. The molecule of claim 1 , wherein the effector molecules are selected independently from the group consisting of siRNA, snRNA, antisense oligonucleotide, ribozyme, and any combinations thereof.
4. The molecule of claim 1 , wherein one of said at least two effector molecules modulate gene expression of a first target nucleic acid and another one of said at least two effector molecules modulates gene expression of a second nucleic acid.
5. The molecule of claim 4 , wherein the first target nucleic acid and the second target nucleic acid are the same.
6. The molecule of claim 5 , wherein the first target nucleic acid comprises a nucleotide sequence identical to the nucleotide sequence of the second target nucleic acid.
7. The molecule of claim 2 , wherein the ligand is conjugated at a 3′-end of one of said at least two effector molecules.
8. The molecule of claim 2 , wherein the ligand is conjugated at a 5′-end of one of said at least two effector molecules.
9. The molecule of claim 1 , wherein one of said at least two effector molecules is a first double-stranded siRNA molecule comprising a sense strand and an antisense strand, and another one of said at least two effector molecules is a second double-stranded siRNA molecule comprising a sense strand an antisense strand.
10. The molecule of claim 9 , wherein the sense strand of the first siRNA molecule is covalently linked to the sense strand of the second siRNA molecule.
11. The molecule of claim 9 , wherein the sense strand of the first siRNA molecule is covalently linked to the antisense strand of the second siRNA molecule.
12. The molecule of claim 9 , wherein the antisense strand of the first siRNA molecule is covalently linked to the antisense strand of the second siRNA molecule.
13. The molecule of claim 9 , wherein a ligand is conjugated with one of the sense strands.
14. The molecule of claim 9 , wherein a ligand is conjugated with one of the antisense strands.
15. The molecule of claim 9 , wherein the molecule comprises at least one modification selected from the group consisting of modified internucleoside linkage, modified nucleobase, modified sugar, and any combinations thereof.
16. The molecule of claim 15 , wherein said at least one modification is comprised in a sense strand or an antisense strand.
17. The molecule of claim 1 , wherein the linker is selected from the group consisting of
18. The molecule of claim 17 , wherein the linker is selected from the group consisting of Q303, Q304, Q305, Q306, Q312, Q313, Q314, Q315, Q316 and Q317.
19. The molecule of claim 18 , wherein the linker is Q304.