Antisense Oligomer Conjugates for Exon 53 Skipping
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Solution Overview
Problem
Current antisense oligomers for treating Duchenne muscular dystrophy (DMD) are not effective in targeting exon 53, which is crucial for restoring dystrophin production in DMD patients.
Innovation Solution
Development of novel antisense oligomers and their conjugates with cell-penetrating peptides (CPPs) that specifically target exon 53 in the dystrophin gene, allowing for effective exon skipping and restoration of dystrophin production.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional antisense oligomers are used to target exon 53, then the oligomers can bind to the target RNA sequence, but they fail to effectively induce exon skipping and restore dystrophin production
Solution Approach 1:
The patent applies composite materials by combining antisense oligomers with cell-penetrating peptides (CPPs) to create a hybrid molecule that possesses both RNA-binding capability and enhanced cellular uptake properties. This composite structure resolves the contradiction by enabling the oligomer to effectively enter cells and induce exon skipping, thereby restoring dystrophin production in DMD patients.
Solution Approach 2:
The patent employs parameter changes by modifying the chemical structure of conventional antisense oligomers through conjugation with CPPs. This structural modification alters key parameters including cellular permeability, subcellular localization, and biological activity, transforming the oligomer from an ineffective conventional molecule into an effective therapeutic agent that can induce exon skipping and restore dystrophin production.
2Reliability
If antisense oligomers are designed to be longer for better target binding, then binding affinity increases, but cellular uptake and delivery efficiency decrease
Solution Approach 1:
The patent merges two distinct functional components: the antisense oligomer (providing target binding affinity) and the cell-penetrating peptide (providing cellular uptake efficiency). This merging resolves the contradiction by creating a single conjugate molecule that simultaneously achieves both high target binding affinity and efficient cellular delivery, eliminating the need to choose between these competing properties.
Solution Approach 2:
The cell-penetrating peptide acts as an intermediary that facilitates the delivery of the antisense oligomer into cells. This intermediary component resolves the contradiction by enabling efficient cellular uptake of the oligomer without compromising its target binding capability, effectively bridging the gap between extracellular delivery and intracellular target engagement.
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 novel antisense oligomers and conjugates induce significant exon 53 skipping, leading to the production of functional dystrophin protein, thereby providing a therapeutic benefit for DMD patients.
Implementation Method 1
antisense oligomers and antisense oligomer conjugates which include an antisense oligomer moiety conjugated to a cell-penetrating peptide (CPP)... an antisense oligomer of 18-25 subunits in length capable of binding a selected target to induce exon skipping in the human dystrophin gene
Data Source
AI summary
Antisense oligomers and antisense oligomer conjugates complementary to a selected target site in the human dystrophin gene to induce exon 53 skipping are described.