Granted Patent
B2
US 12,385,041 · App. 16/638,107 · Granted Aug 12, 2025
Conditional-siRNAS and uses thereof in treating cardiac hypertrophy
Inventors:
Saumya Das (Boston, MA); Ane Miren Salvador Garicano (Boston, MA); Si-ping Han (Duarte, CA); Lisa Scherer (Duarte, CA); Julia Derogatis (Duarte, CA); Robin Hu (Duarte, CA); Sahil Sagar (Duarte, CA); William A. Goddard, III (Pasadena, CA); John Rossi (Duarte, CA)
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Abstract
Disclosed herein are conditional siRNAs activatable by pro-hypertrophic RNA sequences and use thereof for treating conditions such as cardiac hypertrophy. The conditional siRNAs target calcineurin or HDAC2.
Claims (43)
1. A conditional RNA-sensor complex comprising:
a sensor strand comprising at least one toehold segment, wherein the toehold segment capable of binding a pathological biomarker present in or overexpressed in a target cell, wherein the pathological biomarker comprises a molecule that encodes ANP, BNP, MHCβ, mir-23a-3p, mir-125-6p, or mir-199b-5p; and
a double stranded pro-RNA molecule comprising
a guide strand comprising an RNA molecule capable of binding a therapeutic target molecule in the target cell, wherein the therapeutic target molecule is an RNA molecule that encodes calcineurin or histone deacetylase 2 (HDAC2); 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-RNA molecule when the pathological biomarker binds the toehold segment and the resulting double stranded pro-RNA molecule is a substrate for Dicer.
5. The conditional RNA-sensor complex of claim 1 , wherein the target cell is a cardiac myocyte.
6. The conditional RNA-sensor complex of claim 1 , wherein the molecule that encodes ANP, BNP, or MHCβ is an mRNA molecule and the molecule that encodes mir-23a-3p, mir-125-6p, or mir-199b-5p is an miRNA molecule.
7. The conditional RNA-sensor complex of claim 6 , wherein the molecule that encodes ANP comprises a sequence selected from SEQ ID Nos: 8-10, the molecule that encodes BNP comprises a sequence selected from SEQ ID Nos: 4-6, the molecule that encodes MHCβ comprises a sequence of SEQ ID NO: 7, and the molecule that encodes mir-23a-3p comprises a sequence selected from SEQ ID Nos: 1-3.
8. The conditional RNA-sensor complex of claim 7 , wherein the sensor 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.
9. The conditional RNA-sensor complex of claim 5 , wherein the double stranded pro-RNA molecule is an RNA interference (RNAi) molecule.
10. The conditional RNA-sensor complex of claim 9 , wherein the guide strand comprises a sequence selected from SEQ ID NOS: 11-16.
11. The conditional RNA-sensor complex of claim 2 , wherein the first linker, the second linker, or both the first and second linkers is a C3 spacer.
12. The conditional RNA-sensor complex of claim 9 , wherein the guide 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 2 , 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.
14. The conditional RNA-sensor complex of claim 13 , wherein the core strand comprises a sequence selected from SEQ ID NOS: 17-26.
15. The conditional RNA-sensor complex of claim 13 , wherein 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.
16. The conditional RNA-sensor complex of claim 1 , wherein:
(a) the sensor strand comprises a sequence having at least 95% homology to SEQ ID NO:4, the core strand comprises a sequence having at least 95% homology to SEQ ID NO:21, SEQ ID NO: 49, and SEQ ID NO: 50, and the guide strand comprises a sequence having at least 95% homology to SEQ ID NO:15;
(b) the sensor strand comprises a sequence having at least 95% homology to SEQ ID NO:5, the core strand comprises a sequence having at least 95% homology to SEQ ID NO:22, SEQ ID NO: 49, and SEQ ID NO: 51, and the guide strand comprises a sequence having at least 95% homology to SEQ ID NO:15;
(c) the sensor strand comprises a sequence having at least 95% homology to SEQ ID NO:6, the core strand comprises a sequence having at least 95% homology to SEQ ID NO:23, SEQ ID NO: 49, and SEQ ID NO: 52, and the guide strand comprises a sequence having at least 95% homology to SEQ ID NO:15;
(d) the sensor strand comprises a sequence having at least 95% homology to SEQ ID NO:7, the core strand comprises a sequence having at least 95% homology to SEQ ID NO:24, SEQ ID NO: 49, and SEQ ID NO: 53, and the guide strand comprises a sequence having at least 95% homology to SEQ ID NO:15;
(e) the sensor strand comprises a sequence having at least 95% homology to SEQ ID NO:8, the core strand comprises a sequence having at least 95% homology to SEQ ID NO:25, and the guide strand comprises a sequence having at least 95% homology to SEQ ID NO:16;
(f) the sensor strand comprises a sequence having at least 95% homology to SEQ ID NO:8, the core strand comprises a sequence having at least 95% homology to SEQ ID NO:18, SEQ ID NO: 45, and SEQ ID NO: 47, and the guide strand comprises a sequence having at least 95% homology to SEQ ID NO:11;
(g) the sensor strand comprises a sequence having at least 95% homology to SEQ ID NO:10, the core strand comprises a sequence having at least 95% homology to SEQ ID NO:19, SEQ ID NO: 45, and SEQ ID NO: 48, and the guide strand comprises a sequence having at least 95% homology to SEQ ID NO:12;
(h) the sensor strand comprises a sequence having at least 95% homology to SEQ ID NO:1, the core strand comprises a sequence having at least 95% homology to SEQ ID NO: 41, SEQ ID NO: 45, and SEQ ID NO: 56, and the guide strand comprises a sequence having at least 95% homology to SEQ ID NO:12;
(i) the sensor strand comprises a sequence having at least 95% homology to SEQ ID NO:2, the core strand comprises a sequence having at least 95% homology to SEQ ID NO: 41, SEQ ID NO: 45, and SEQ ID NO: 56, and the guide strand comprises a sequence having at least 95% homology to SEQ ID NO: 12; or
(j) the sensor strand comprises a sequence having at least 95% homology to SEQ ID NO:39, the core strand comprises a sequence having at least 95% homology to SEQ ID NO: 41, SEQ ID NO: 45, and SEQ ID NO: 56, and the guide strand comprises a sequence having at least 95% homology to SEQ ID NO:12.
17. The conditional RNA-sensor complex of claim 16 , 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.
18. A pharmaceutical composition comprising:
a conditional RNA-sensor complex of claim 1 ; and
a pharmaceutically acceptable carrier or excipient.
19. 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, wherein the pathological condition is myocardial infarction (MI), or cardiac hypertrophy.
20. The method of claim 19 , wherein administering a therapeutically effective amount comprises an intramyocardial injection of the conditional RNA-sensor complex or the pharmaceutical composition after detection of MI.
21. The conditional RNA-sensor complex of claim 1 , wherein the passenger strand bound to the guide strand forms a duplex between 15 and 30 base pairs in length.
Assignments (4)
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Jan 13, 2022
From: SALVADOR GARICANO, ANE MIREN; DAS, SAUMYA
To: THE GENERAL HOSPITAL CORPORATION
Reel/Frame 058650/0782 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Nov 1, 2021
From: HAN, SI-PING; SCHERER, LISA; DEROGATIS, JULIA; HU, ROBIN; SAGAR, SAHIL; ROSSI, JOHN
To: CITY OF HOPE
Reel/Frame 057983/0838 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Jun 2, 2020
From: GODDARD, WILLIAM A., III
To: CALIFORNIA INSTITUTE OF TECHNOLOGY
Reel/Frame 052814/0719 →
CONFIRMATORY LICENSE
Recorded Feb 18, 2020
From: CALIFORNIA INSTITUTE OF TECHNOLOGY
To: NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT
Reel/Frame 051848/0111 →
Continuity (2)
Provisional Application
62543882
· Aug 10, 2017
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