Antisense Oligomer Splicing Modulation for Type VII Collagen
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Solution Overview
Problem
Current treatments for dystrophic epidermolysis bullosa (DEB) are inadequate in increasing functional human type VII collagen protein levels, leading to severe skin blistering and increased risk of skin cancer, as existing methods fail to effectively target and correct the genetic mutations causing structural defects in anchoring fibrils.
Innovation Solution
Development of antisense oligomers that specifically target and modify the splicing of human type VII collagen pre-mRNA, specifically excluding exon 80 to increase the expression of functional type VII collagen protein by binding to the exon/intron splice junction, thereby enhancing the production of mature mRNA that maintains an open reading frame and promotes the formation of functional anchoring fibrils.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If conventional treatment methods are used for dystrophic epidermolysis bullosa, then treatment simplicity is maintained, but functional type VII collagen protein levels remain insufficient
Solution Approach 1:
Antisense oligomers serve as intermediary molecules that bind to specific sequences in COL7A1 pre-mRNA to modulate splicing. These oligomers contain modified nucleotides (such as 2'-O-methyl, LNA, or phosphorothioate linkages) that enable specific binding to target sequences, acting as a mediator between the genetic material and the desired splicing outcome, thereby increasing functional collagen protein levels through a targeted molecular mechanism
Solution Approach 2:
The invention changes the splicing parameters of COL7A1 pre-mRNA by introducing antisense oligomers that bind to specific sequences, thereby altering the splicing pattern to exclude harmful exons (exon 80 or exon 99) or include missing exons. This parameter change in gene expression leads to production of functional type VII collagen protein with corrected structure
2Quantity of substance
If antisense oligomers target exon/intron splice junctions to exclude harmful exons, then functional collagen protein expression increases, but treatment specificity requirements increase
Solution Approach 1:
The antisense oligomers are designed with specific local sequences that match complementary sequences at exon/intron splice junctions of COL7A1 pre-mRNA. By targeting specific local regions (such as the 5' splice site of exon 80 or the 3' splice site of exon 99), the oligomers achieve precise local modification of splicing without affecting other parts of the transcript, thereby excluding harmful exons while maintaining overall transcript integrity
Solution Approach 2:
The COL7A1 pre-mRNA is segmented into functional units (exons and introns), and the antisense oligomers specifically target and modify the splicing of particular segments (harmful exons 80 or 99). This segmentation approach allows selective exclusion of pathogenic exons while preserving the splicing and function of other essential exons, achieving precision through modular control of splicing events
3Reliability
If current treatments fail to correct genetic mutations, then treatment simplicity is maintained, but disease severity progression continues
Solution Approach 1:
The antisense oligomers perform preliminary action by binding to COL7A1 pre-mRNA before the harmful exons are incorporated into the mature mRNA. By intervening at the pre-mRNA splicing stage, the oligomers prevent the inclusion of harmful exons (exon 80 or exon 99) or promote the inclusion of missing exons before translation occurs, thereby preventing the production of non-functional or harmful collagen proteins
Solution Approach 2:
The invention replaces conventional mechanical or surgical treatment approaches with a molecular-level biochemical mechanism. Antisense oligomers utilize base-pairing chemistry and splicing modulation to correct the underlying genetic defect, substituting a molecular biochemical system for traditional mechanical interventions, thereby achieving reliable correction of mutation effects
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
The use of antisense oligomers significantly increases the expression of functional type VII collagen protein, improving dermal-epidermal adhesion and reducing the severity of DEB symptoms by enhancing the accumulation of functional anchoring fibrils, potentially reducing the risk of skin cancer.
Implementation Method 1
an antisense oligomer that binds to a target region of a human type VII collagen pre-mRNA transcript
Data Source
AI summary
The present disclosure relates to antisense oligomers and related compositions and methods for increasing the expression of functional human type VII collagen and methods for treating dystrophic epidermolysis bullosa and related disorders and relates to inducing exclusion of exon 80 in human type VII collagen mRNA.