Conditional-siRNAs and uses thereof in treating acute myeloid leukemia
Disclosed herein are conditional siRNAs activatable by CBFβ-MYH11 oncogenic gene and use thereof for treating conditions such as acute myeloid leukemia (AML). The conditional siRNAs target MCL-1 or HDAC8.
1 . A conditional RNA-sensor complex comprising:
a sensor strand comprising at least one toehold segment, wherein the toehold segment binds a pathological biomarker that is associated with acute myeloid leukemia (AML) and present in or overexpressed in a target cell, wherein the sensor strand comprises a sequence having at least 95% homology to SEQ ID NO:1; and
a double stranded pro-siRNA molecule comprising
a guide strand comprising an RNA molecule that binds a therapeutic target molecule in the target cell, wherein the therapeutic target molecule is MCL-1 or HDAC8; and
a core strand comprising
a first portion comprising a passenger strand that is fully or partially complimentary to and binds the guide strand;
a second portion comprising a first protection segment that is fully or partially complimentary to and binds the sensor strand; and
a first linker that joins a first end of the passenger strand to the first protection segment.
2 . The conditional RNA-sensor complex of claim 1 , wherein the core strand further comprises a third portion comprising a second protection segment that is fully or partially complimentary to and binds the sensor strand, and a second linker that joins a second end of the passenger strand to the second protection segment.
3 . The conditional RNA-sensor complex of claim 1 , wherein the toehold segment is an aptamer.
4 . The conditional RNA-sensor complex of claim 1 , wherein the sensor strand is displaced from the double stranded pro-siRNA molecule when the pathological biomarker binds the toehold segment and the resulting double stranded pro-siRNA molecule is a substrate for Dicer.
5 . The conditional RNA-sensor complex of claim 1 , wherein the target cell is a cancer cell.
6 . The conditional RNA-sensor complex of claim 5 , wherein the pathological biomarker is a biomarker associated with acute myeloid leukemia (AML).
7 . The conditional RNA-sensor complex of claim 6 , wherein the pathological biomarker comprises a molecule that encodes a portion of CBFβ-MYH11.
8 . The conditional RNA-sensor complex of claim 7 , wherein the sensor strand comprises SEQ ID NO:1.
9 . The conditional RNA-sensor complex of claim 7 , wherein the guide strand comprises a sequence selected from SEQ ID NOS: 2-3.
10 . The conditional RNA-sensor complex of claim 5 , wherein the core strand comprises
a passenger strand;
a first linker that joins a 3′ end of the passenger strand to the first protection segment; and
a second linker that joins a 5′ end of the passenger strand to the second protection segment.
11 . The conditional RNA-sensor complex of claim 10 , wherein the core strand comprises SEQ ID NOs: 4, 5 and 6.
12 . The conditional RNA-sensor complex of claim 8 , wherein the sensor strand, the guide strand and/or the core strand further comprises one or more chemical modifications to the RNA sequence, wherein the one or more chemical modifications are selected from a locked nucleic acid (LNA) modification, a peptide nucleic acid (PNA) modification, a 2′-O-methyl modification, morpholino modification, a phosphorothioate modification, a terminal modification, or a linker modification.
13 . The conditional RNA-sensor complex of claim 1 , wherein the core strand comprises a sequence having at least 95% homology to SEQ ID NOs: 4, 5 and 6, and the guide strand comprises a sequence having at least 95% homology to SEQ ID NO:2.
14 . The conditional RNA-sensor complex of claim 13 , wherein the sensor strand, the guide strand and/or the core strand further comprises one or more chemical modifications to the RNA sequence, wherein the one or more chemical modifications are selected from a locked nucleic acid (LNA) modification, a peptide nucleic acid (PNA) modification, a 2′-O-methyl modification, morpholino modification, a phosphorothioate modification, a terminal modification, or a linker modification.
15 . The conditional RNA-sensor complex of claim 7 , wherein the toehold segment is capable of binding to a least a portion of the sequence of SEQ ID NO: 13.
16 . The conditional RNA-sensor complex of claim 7 , wherein the pathological biomarker comprises the sequence of SEQ ID NO: 13.
17 . A pharmaceutical composition comprising:
a conditional RNA-sensor complex of claim 1 ; and
a pharmaceutically acceptable carrier or excipient.
18 . A method of treating a pathological condition comprising administering a therapeutically effective amount of a conditional RNA-sensor complex of claim 1 to a subject suffering from the pathological condition.
19 . The method of claim 18 , wherein the pathological condition is acute myeloid leukemia (AML).