Conditional-siRNAS and uses thereof in treating cardiac hypertrophy
Inventors
DAS, Saumya • SALVADOR GARICANO, Ane Miren • Han, Si-Ping • SCHERER, Lisa • DEROGATIS, Julia • Hu, Robin • Sagar, Sahil • Goddard, III, William A. • Rossi, John
Assignees
General Hospital Corp • California Institute of Technology • City of Hope
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Publication Number
US-12385041-B2
Publication Date
2025-08-12
Expiration Date
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.
Core Innovation
The invention relates to a conditional RNA-sensor complex that conditionally activates RNA therapeutic activity in a target cell. The complex includes a sensor strand with at least one toehold segment capable of binding a pathological biomarker present in or overexpressed in the target cell. The pathological biomarker comprises a molecule that encodes ANP, BNP, MHCβ, or specific miRNAs, including mir-23a-3p, mir-125-6p, or mir-199b-5p.
The complex further comprises a double stranded pro-RNA molecule having a guide strand and a core strand configured to couple a therapeutic-target binding function to biomarker-dependent activation. The guide strand comprises an RNA molecule capable of binding a therapeutic target molecule in the target cell, where the therapeutic target molecule is an RNA molecule that encodes calcineurin or histone deacetylase 2 (HDAC2). The core strand comprises a first portion with a passenger strand that is fully or partially complimentary to and binds the guide strand, and a second portion with a first protection segment that is fully or partially complimentary to and binds the sensor strand, connected by a first linker joining a first end of the passenger strand to the first protection segment.
In the disclosed examples and rationale, the conditional sensor and the pro-RNA architecture convert an OFF pro-siRNA into an ON siRNA in a disease-relevant context. Biomarker binding is associated with toehold-mediated strand displacement such that the resulting double stranded pro-RNA molecule functions as a substrate for Dicer, enabling incorporation into RISC and downstream processing. The patent context ties this conditional RNA-sensor concept to pathological cardiac hypertrophy, including myocardial infarction and ischemia-related biomarker expression, and specifies calcineurin and HDAC2 as therapeutic targets.
Claims Coverage
The disclosure is anchored by one independent claim defining a conditional RNA-sensor complex. The claim contains multiple inventive structural features, including the sensor strand with a toehold for binding specified pathological biomarker-encoding molecules and a double stranded pro-RNA molecule with a guide strand for binding therapeutic-target-encoding RNA molecules linked via complementary passenger and protection segments.
Toehold-based sensor binding of pathological biomarker-encoding molecules
A sensor strand comprising at least one toehold segment, wherein the toehold segment is 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.
Guide strand targeting therapeutic RNA encoding calcineurin or HDAC2
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).
Core strand coupling passenger and protection segments via a linker
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.
Overall claim coverage centers on a biomarker-responsive conditional RNA-sensor complex that couples a toehold-bearing sensor strand specific for biomarkers encoding ANP/BNP/MHCβ or specified miRNAs to a double stranded pro-RNA molecule containing a guide strand directed to RNA therapeutic targets encoding calcineurin or HDAC2, with activation or functional coupling mediated by the core strand’s complementary passenger and protection segments connected by a linker.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Not explicitly described in patent.
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