Intronic REMS Recognition for RNA Splicing Modulation
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Solution Overview
Problem
Current methods for treating diseases associated with aberrant gene expression often focus on post-translational targets, whereas targeting the splicing process with small molecules can more effectively address the underlying cause by modulating aberrant RNA transcripts before protein production.
Innovation Solution
The use of a recognition element for splicing modifier (REMS) present in introns, recognized by the U1 snRNP and other splicing machinery components, in conjunction with small molecule splicing modifiers, to induce alternative splicing of intronic exons, thereby modulating gene expression and protein production.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If post-translational targets are used for treating diseases associated with aberrant gene expression, then treatment can be implemented, but the underlying cause of the disease is not effectively addressed and treatment efficiency is reduced
Solution Approach 1:
The patent applies preliminary action by targeting the splicing process before protein translation occurs. Small molecule splicing modifiers are used to alter RNA splicing patterns, preventing the formation of aberrant gene products at the RNA level. This upstream intervention addresses the root cause of diseases caused by aberrant gene expression, rather than treating post-translational effects, thereby improving both treatment reliability and efficiency
2Reliability
If small molecule splicing modifiers are used to target the splicing process, then the underlying cause of disease can be addressed, but the complexity of the splicing machinery requires precise targeting
Solution Approach 1:
The patent applies local quality by designing small molecule splicing modifiers that target specific local sites within the splicing machinery. These compounds are engineered to bind to particular sequences or structures in pre-mRNA or splicing factors, enabling selective modulation of specific splicing events rather than global splicing inhibition. This localized targeting approach manages the complexity of the splicing system while achieving reliable disease treatment
Solution Approach 2:
The patent uses small molecule splicing modifiers as intermediaries between the researcher and the complex splicing machinery. These small molecules serve as mediators that can selectively bind to and modulate specific components of the splicing apparatus, translating complex molecular interactions into controllable therapeutic effects. This intermediary approach simplifies the management of splicing complexity while maintaining treatment reliability
Data Source
AI summary
In one aspect, described herein is an intronic recognition element for splicing modifier (iREMS) that can be recognized by a compound provided herein. In another aspect, described herein are methods for modulating the amount of a product of a gene, wherein a precursor RNA transcript transcribed from the gene contains an intronic REMS, and the methods utilizing a compound described herein. More particularly, described herein are methods for modulating the amount of an RNA transcript or protein product encoded by a gene, wherein a precursor RNA transcript transcribed from the gene comprises an intronic REMS, and the methods utilizing a compound described herein. In another aspect, provided herein are artificial gene constructs comprising an intronic REMS, and uses of those artificial gene constructs to modulate protein production. In another aspect, provided herein are methods for altering endogenous genes to comprise an intronic REMS, and the use of a compound described herein to modulate protein produced from such altered endogenous genes.