REMS RNA Splicing Modulation via U1 snRNP Interaction
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Solution Overview
Problem
Current treatments for diseases associated with aberrant RNA transcript levels often focus on protein expression rather than addressing the underlying causes, such as splicing process perturbations or transcription factor abnormalities, which limits their effectiveness in modulating RNA transcript amounts.
Innovation Solution
The introduction of a recognition element for splicing modifier (REMS) into DNA or RNA sequences, specifically with nucleotide sequences like GAgurngn or ANGAgurngn, to alter splicing patterns and modulate RNA transcript levels, using compounds that enhance the interaction with U1 snRNP, thereby affecting the splicing outcome and protein production.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If treatments focus on protein expression to address diseases with aberrant RNA transcript levels, then protein levels can be modulated, but the underlying causes such as splicing process perturbations remain unaddressed
Solution Approach 1:
The patent introduces splicing modifiers as intermediary compounds that specifically target splicing processes. These compounds act as mediators between the aberrant splicing events and the desired therapeutic outcome, allowing precise intervention at the splicing level rather than broadly affecting protein expression. The splicing modifiers bind to specific RNA sequences or splicing factors to correct abnormal splicing patterns, thereby addressing the root cause while maintaining treatment effectiveness.
Solution Approach 2:
The patent extracts and targets the specific splicing process perturbations that cause aberrant RNA transcript levels. By identifying and isolating the defective splicing events as the primary target, the treatment can specifically correct these perturbations without needing to address the entire protein expression pathway. This extraction of the core problem (splicing defects) allows for more precise and effective therapy.
2Reliability
If splicing modifiers are used to target splicing process perturbations, then the root cause of aberrant RNA levels can be addressed, but the complexity of identifying and targeting specific splicing defects increases
Solution Approach 1:
The patent applies local quality by designing splicing modifiers that target specific local sequences or structural features within the RNA molecule. Rather than attempting to detect and correct all splicing defects globally, the approach focuses on identifying particular local splicing perturbations (such as specific exon-intron boundaries or regulatory sequences) and developing modifiers that specifically address these localized defects. This localized targeting simplifies the detection and measurement process while maintaining high treatment effectiveness.
3Ease of operation
If traditional treatments focus on protein expression rather than splicing processes, then the approach is simpler, but the ability to modulate RNA transcript amounts is limited
Solution Approach 1:
The patent introduces dynamics by enabling adjustable and tunable modulation of splicing processes. Splicing modifiers can be designed with varying affinities and specificities to achieve different degrees of RNA transcript modulation. This dynamic approach allows treatment to be optimized for different disease states and patient conditions, providing versatility in modulating RNA transcript levels while maintaining operational simplicity through a unified therapeutic platform.
Data Source
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AI summary
In one aspect, described herein is a recognition element for splicing modifier (REMS) 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 a 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 a REMS, and the methods utilizing a compound described herein. In another aspect, provided herein are artificial gene constructs comprising a REMS, and uses of those artificial gene constructs to modulate functional protein production. In another aspect, provided herein are methods for altering endogenous genes to comprise a REMS, and the use of a compound described herein to modulate the functional protein produced from such altered endogenous genes.