Exon 51 Antisense Oligomers for Targeted Dystrophin Exon Skipping
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Solution Overview
Problem
There is a need for antisense oligomers that target exon 51 to induce exon skipping in the human dystrophin gene for therapeutic methods to produce dystrophin and treat Duchenne muscular dystrophy (DMD).
Innovation Solution
Development of antisense oligomers with specific base sequences complementary to the exon 51 target region of the dystrophin pre-mRNA, capable of inducing exon skipping, and conjugated with cell-penetrating peptides for effective delivery.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If antisense oligomers are designed to target exon 51, then exon skipping is induced and functional dystrophin production is facilitated, but the complexity of oligomer sequence design and selection increases
Solution Approach 1:
The dystrophin gene is segmented into multiple exons, with exon 51 being a specific target segment. The antisense oligomers are designed to specifically target and bind to this segmented exon 51 region, inducing skipping of this particular segment while preserving other exons. This segmentation approach enables precise control over which portion of the gene is modified.
Solution Approach 2:
Different regions of the dystrophin pre-mRNA are treated differently through localized antisense oligomer binding. The oligomers are designed with specific base sequences that are complementary to specific regions of exon 51, creating local areas of high affinity binding that trigger exon skipping only in the targeted region rather than uniformly across the entire gene.
2Measurement precision
If multiple antisense oligomer sequences are evaluated and selected, then the optimal target binding is achieved, but the time and computational resources required for sequence selection increase
Solution Approach 1:
Instead of exhaustively evaluating all possible oligomer sequences, the methodology uses computational algorithms to generate and filter a partial set of candidate sequences based on predefined criteria such as binding affinity, specificity, and compatibility with the target region. This partial action approach achieves sufficient precision for therapeutic application while significantly reducing the time and computational resources required compared to complete exhaustive search.
3Ease of operation
If antisense oligomers are conjugated with cell-penetrating peptides, then delivery to target cells is improved, but the complexity of the oligomer-conjugate structure increases
Solution Approach 1:
Cell-penetrating peptides serve as intermediary molecules that bridge the gap between the antisense oligomer and the target cell. The peptide conjugate acts as a mediator that facilitates transport of the oligomer through the cell membrane and into the cytoplasm, where it can then bind to the dystrophin pre-mRNA. This intermediary approach improves delivery efficiency without requiring direct modification of the oligomer's core binding function.
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 antisense oligomers facilitate the production of functional dystrophin by maintaining the correct reading frame, potentially treating DMD and Becker muscular dystrophy.
Implementation Method 1
the antisense oligomer, or a pharmaceutically acceptable salt thereof, comprises a sequence of bases that is complementary to an exon 51 target region of the dystrophin pre-mRNA designated as an annealing site
Data Source
AI summary
Antisense oligomers complementary to a selected target site in the human dystrophin gene to induce exon 51 skipping are described.