ExSpeU1 snRNA for Selective Splicing Correction
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Solution Overview
Problem
Current therapies for genetic diseases caused by aberrant splicing defects, such as hemophilia B, cystic fibrosis, and spinal muscular atrophy, face limitations in efficacy and specificity, particularly due to non-specific action of therapeutic snRNA molecules that can interfere with wild-type gene transcripts and require multiple modified U1snRNA molecules for different mutations.
Innovation Solution
Development of Exon Specific U1 (ExSpeU1) snRNA molecules that bind to target nucleotide sequences within intron regions downstream of the 5' splicing site, allowing for selective correction of exon skipping caused by various mutations, including those in donor, acceptor, and exonic sites, using a single modified U1snRNA for multiple genetic mutations.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If modified U1snRNA molecules are used to correct splicing defects, then splicing correction efficacy is improved, but non-specific interference with wild-type transcripts occurs
Solution Approach 1:
The patent applies local quality by designing the 5' single-stranded region of U1snRNA to specifically recognize and bind only to mutated splicing sites. The modified nucleotide sequence in this region is tailored to match the specific mutation (e.g., corrected donor sites), enabling the therapeutic U1snRNA to selectively correct aberrant splicing at mutant sites while leaving wild-type transcripts unaffected. This localized specificity resolves the contradiction between achieving splicing correction and avoiding non-specific interference.
2Adaptability or versatility
If multiple modified U1snRNA molecules are used to cover different mutations, then coverage of genetic mutations is improved, but device complexity increases
Solution Approach 1:
The patent implements universality by creating a single modified U1snRNA molecule that can address multiple mutation types through its designed 5' single-stranded region. By engineering this region to recognize conserved sequences or patterns across different mutations (such as common donor site mutations), one therapeutic U1snRNA can correct multiple splicing defects. This multi-functional approach reduces the number of different U1snRNA molecules needed while maintaining broad mutation coverage, thereby reducing device complexity.
3Reliability
If current hemophilia B therapy with frequent infusion is used, then therapeutic effect is maintained, but treatment burden and cost increase
Solution Approach 1:
The patent applies preliminary action by introducing therapeutic U1snRNA molecules that permanently or long-term correct the splicing defect at the molecular level. Once the corrected U1snRNA is introduced (via transfection or viral vector delivery), it continuously produces functional mRNA from the mutated gene, establishing long-lasting therapeutic effects. This eliminates the need for frequent infusions required by conventional protein replacement therapy, as the splicing correction is sustained over time through endogenous gene expression.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
ExSpeU1 snRNA molecules demonstrate targeted and selective action, effectively restoring correct splicing in disease models like hemophilia B, cystic fibrosis, and spinal muscular atrophy, with potential for long-lasting therapeutic effects by increasing exon inclusion and reducing non-specific interference with wild-type transcripts.
Implementation Method 1
a modified U1snRNA molecule which binds to a target nucleotide sequence on a primary transcript of a target gene
Data Source
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AI summary
A modified human U1snRNA molecule is described, the target sequence of which is located in a region of the pre-mRNA of the target gene comprised between 2 and 50 base pairs downstream of an exon/intron junction site, which is capable of restoring the correct splicing of a target gene of therapeutic interest bearing a mutation which induces exon skipping and resulting in a genetic disease. Modified human U1snRNA molecules are described by way of example for the correction of diseases associated with exon skipping, such as spinal muscular atrophy, hemophilia B, and cystic fibrosis.