Exonic Splicing Regulatory Hexamer Targeting for Aberrant Pre-mRNA Correction
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Solution Overview
Problem
Current methods fail to effectively identify and address aberrant pre-mRNA splicing caused by disease-related mutations, which are often misinterpreted as impacting protein structure rather than splicing, due to the functional overlap between splicing regulation elements and protein coding sequences.
Innovation Solution
Development of methods and compounds that target specific regulatory hexamers such as ACUAGG, CUUAGG, AUUAGG, UAGGUA, or GUAGUU to interfere with aberrant splicing by competing with cis-acting elements or using siRNA to block their function, allowing for proper splicing restoration and phenotype rescue.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If current methods are used to identify disease-related mutations, then mutations are identified, but they are misinterpreted as impacting protein structure rather than splicing
Solution Approach 1:
The patent applies preliminary action by pre-defining and cataloging splicing regulatory elements (exonic splicing enhancers and silencers) and their characteristic sequences before analyzing disease mutations. This allows mutations to be evaluated against known splicing patterns in advance, preventing misinterpretation of their functional impact on splicing versus protein structure.
Solution Approach 2:
The patent introduces computational algorithms and databases of splicing regulatory elements as intermediaries between raw mutation data and biological interpretation. These intermediaries systematically evaluate whether mutations affect splicing regulatory sequences, serving as a bridge that prevents direct but erroneous interpretation of mutations as purely protein-structure affecting.
2Adaptability or versatility
If there is functional overlap between splicing regulation elements and protein coding sequences, then both functions are present in the same sequence, but it becomes difficult to distinguish their respective impacts
Solution Approach 1:
The patent segments the analysis of exonic sequences by identifying and separating splicing regulatory elements from protein-coding regions within the same exon. By cataloging specific sequence patterns characteristic of exonic splicing enhancers and silencers, the method divides the functional analysis into distinct components, allowing independent evaluation of splicing regulatory function versus protein-coding function.
Solution Approach 2:
The patent applies local quality by examining specific local sequence patterns within exons that are characteristic of splicing regulatory elements. Rather than treating the entire exon uniformly, the method identifies localized regions with specific sequence motifs (such as hexamers like ACUAGG, CUUAGG, AUUAGG) that have splicing regulatory function, distinguishing these local regulatory regions from the surrounding protein-coding sequence.
3Reliability
If compounds are designed to interfere with regulatory hexamers, then aberrant splicing is blocked, but specificity of targeting must be ensured
Solution Approach 1:
The patent applies copying by creating compounds that are complementary copies or analogs of the target regulatory hexamer sequences. These compounds (such as antisense oligonucleotides or small molecules designed to bind specific hexamers like ACUAGG, CUUAGG, AUUAGG, UAGGUA, or GUAGUU) replicate key structural features of the target sequence to achieve specific binding, thereby blocking aberrant splicing while maintaining sequence-specificity to minimize off-target effects.
Data Source
AI summary
Compounds and methods for regulation of exonic splicing enhancers and exonic splicing silencers. Compounds include polynucleotides targeted to aberrant exonic splicing enhancers and exonic splicing silencers. Compounds and methods for the diagnosis of diseases and conditions associated with aberrant exonic splicing enhancers and exonic splicing silencers. Methods for identifying splicing-sensitive disease mutations, and functional RNA elements as targets for amelioration of aberrant pre-mRNA splicing.