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SBE APTAMERS FOR TREATING IL-17a RELATED DISEASES AND CONDITIONS

A technology for diseases and conditions, applied in the field of SBE aptamers for the treatment of IL-17a-related diseases and conditions

Pending Publication Date: 2020-05-01
THE CLEVELAND CLINIC FOUND
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although multiple mechanisms of mRNA destabilization have been discovered, there are still large gaps in the knowledge of how the mRNAs of inflammatory genes are selectively stabilized and successfully translated in response to inflammatory stimuli such as IL-17 stimulation

Method used

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  • SBE APTAMERS FOR TREATING IL-17a RELATED DISEASES AND CONDITIONS
  • SBE APTAMERS FOR TREATING IL-17a RELATED DISEASES AND CONDITIONS
  • SBE APTAMERS FOR TREATING IL-17a RELATED DISEASES AND CONDITIONS

Examples

Experimental program
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Embodiment 1

[0055] In this example, an exciting novel role for Act1, which functions as a direct RNA-binding protein to stabilize pro-inflammatory genes (including CXCL1, TNF, and GM-CSF) in response to IL-17 stimulation, is reported Originally unstable mRNA. Mutagenesis studies revealed that Act1 directly binds to the stem-loop structure in the 3'UTR of CXCL1, and the SEFIR domain in Act1 is necessary and sufficient for RNA-binding activity. In support of this, an exemplary RNA aptamer containing a stem-loop structure (termed SBE) inhibits Act1 binding to target mRNAs and attenuates IL-17-mediated mRNA stabilization. Moreover, at the same time SBE RNA aptamer inhibited IL-17-induced skin inflammation.

[0056] Although the present invention is not limited to any particular mechanism, and knowledge of the mechanism is not necessary for the practice of the present invention, it is believed that, mechanistically, Act1 binds directly to the mRNA of inflammatory genes to form a link between ...

no. 1 example

[0125] In summary, although the invention is not limited to any particular mechanism, we propose the following model for Actl-RNA binding for IL-17-induced inflammatory responses. Following IL-17 stimulation, multiple signaling pathways, including NFkB and MAPKs, are activated to induce gene transcription of cytokines and chemokines. Act1 then directly binds mRNAs of cytokines and chemokines to stabilize these otherwise unstable mRNAs to produce pro-inflammatory mediators. Binding of Act1 to inflammatory gene mRNAs leads to the formation of multiple RNPs that control different steps of mRNA metabolism. First, Act1 binds to mRNA in the nucleus (RNP1), thereby inhibiting SF2-mediated mRNA degradation by outcompeting the binding of SF2 to mRNA, which is further facilitated by IKKi-mediated phosphorylation of SF2. One of the possible roles of Act1-RNP1 in the nucleus is to protect the degradation and / or retention of nascent nuclear transcripts. Second, Act1 forms RNP (RNP2) in P...

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Abstract

Provided herein are compositions, systems, kits, and methods for treating IL-17a related diseases and conditions using an SBE nucleic acid sequence that binds a SEFIR domain of an ACT1 protein.

Description

[0001] This application claims priority to US Provisional Application 62 / 535,559, filed July 21, 2017, which is hereby incorporated by reference in its entirety. [0002] Statement Regarding Federal Funding [0003] This invention was made with government support under Grant Nos. P01HL103453, P01CA062220, P01 HL 029582, and RG5130A2 / 1 awarded by the National Institutes of Health. The government has certain rights in this invention. technical field [0004] Provided herein are compositions, systems, kits, and methods for treating IL-17a-related diseases and conditions using SBE nucleic acid sequences that bind the SEFIR domain of the ACT1 protein. Background technique [0005] Interleukin 17 (IL-17, also known as IL-17A) is a key signature cytokine of Th17 cells and is also produced by innate immune cells (Harrington et al., 2005; Park et al., 2005; Cua and Tato, 2010 ). Although IL-17 is required for host defense against extracellular microbes (Cho et al., 2010; Conti et ...

Claims

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Application Information

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IPC IPC(8): A61K31/713A61P17/06A61P11/06A61P37/02A61P29/00A61P19/02A61P25/00
CPCC12N15/115C12N2310/16C12N2310/3517A61K31/713A61P37/06C12N2320/30C12N2310/321C12N2310/3521
Inventor 李晓霞T·赫詹洪凌子D·M·德里斯科尔刘彩霓
Owner THE CLEVELAND CLINIC FOUND