Antisense Oligomer Splicing Modulation for COL6A1 Mutation Detection
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Solution Overview
Problem
Current methods for diagnosing and treating Collagen VI-related disorders (COL6-RD) are insufficient, as they fail to identify all causative mutations and provide only temporary relief from symptoms, lacking a permanent cure.
Innovation Solution
The use of antisense oligomers targeted to specific sequences in the COL6A1 gene to modulate splicing and produce normal alpha 1(VI) chain protein, thereby diagnosing and treating individuals with COL6-RD by correcting aberrant splicing caused by mutations in the COL6A1 gene.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If standard genetic testing methods are used to diagnose COL6-RD, then common mutations can be detected, but they fail to identify all causative mutations including those in intronic regions
Solution Approach 1:
The diagnostic approach is segmented into multiple components: (1) detection of known coding region mutations using standard methods, and (2) detection of intronic splice site mutations using targeted sequencing or PCR-based methods. This segmentation allows each method to optimize for its specific target type, improving overall detection accuracy while maintaining versatility across different mutation types.
Solution Approach 2:
The patent employs a multi-functional diagnostic strategy that can detect multiple types of mutations (coding region substitutions, deletions, and intronic splice site mutations) using a unified diagnostic workflow. The system adapts its detection methodology based on the suspected mutation type, making it universally applicable to all COL6A1 mutation types while maintaining high precision for each specific type.
2Object-affected harmful factors
If current treatments for COL6-RD are administered, then symptom relief is provided, but no permanent cure is achieved
Solution Approach 1:
The patent enables preliminary identification of patients with specific intronic mutations (such as c.930+189 C>T) that cause aberrant splicing. By diagnosing these patients early with precise molecular characterization, they can be enrolled in targeted therapeutic trials before irreversible muscle damage occurs, potentially extending treatment effectiveness and delaying disease progression.
Solution Approach 2:
The detailed molecular diagnosis serves as an intermediary between the disease state and treatment selection. By identifying specific mutation types and their impact on splicing, the diagnosis mediates the selection of appropriate therapeutic strategies (such as splice-modulating oligonucleotides for intronic mutations), bridging the gap between symptom management and potential curative approaches.
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
This approach allows for accurate diagnosis and potential treatment of COL6-RD by restoring normal splicing of the COL6A1 gene, leading to improved muscle function and reduced symptom progression.
Implementation Method 1
hybridization of the antisense oligomer to the target sequence in mutated COL6A1 pre-mRNA results in production of normal (wt) alpha 1(VI) chain protein
Data Source
AI summary
A single nucleotide polymorphism (SNP) that results in development of a Type VI collagen, alpha 1 chain-related disorder, and the use of the SNP to identify individuals at risk for developing COL6-related disorders (COL6-RD). Also provided are antisense oligomers for treating individuals at risk for developing COL6-RD, as well as methods for screening compounds for their potential as therapeutic agents.