Antisense Morpholino Compounds for DMD Exon Skipping
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Solution Overview
Problem
Current antisense oligonucleotides have had mixed success in inducing exon skipping in the dystrophin gene, particularly in muscle cells, and there is a need for improved compounds and delivery methods for Duchenne muscular dystrophy (DMD) therapeutic applications.
Innovation Solution
The development of antisense compounds comprising morpholino subunits with phosphorus-containing intersubunit linkages, designed to hybridize with dystrophin pre-mRNA and induce exon skipping, along with peptide conjugates for enhanced muscle delivery.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If traditional antisense oligonucleotides are used to target dystrophin pre-mRNA, then gene expression can be modulated, but exon skipping efficiency in muscle cells is insufficient
Solution Approach 1:
The patent modifies the chemical parameters of antisense oligonucleotides by incorporating morpholino subunits with phosphorus-containing intersubunit linkages instead of traditional phosphodiester bonds. This chemical parameter change enhances the oligonucleotide's stability and binding affinity to dystrophin pre-mRNA, thereby improving exon skipping efficiency in muscle cells while maintaining the ability to modulate gene expression
Solution Approach 2:
The invention creates composite antisense compounds by combining morpholino subunits with phosphorus-containing linkages and conjugating them to peptide moieties. This composite structure integrates the advantages of morpholino chemistry (enhanced stability and binding) with peptide delivery capabilities, resulting in improved exon skipping efficiency and functional dystrophin production in muscle cells
2Reliability
If antisense compounds are designed to induce exon skipping, then defective gene transcripts can be corrected, but delivery to muscle cells remains challenging
Solution Approach 1:
The patent introduces peptide conjugates as intermediary carriers that facilitate the delivery of antisense compounds to muscle cells. The peptide moiety acts as a mediator that enhances cellular uptake and targeting specificity, enabling the antisense compound to reach its target (dystrophin pre-mRNA) in muscle cells more effectively while maintaining exon skipping induction capability
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
These antisense compounds effectively induce exon skipping in the dystrophin gene, allowing muscle cells to produce functional dystrophin protein, thereby potentially treating DMD and Becker muscular dystrophy (BMD).
Implementation Method 1
antisense compounds comprising morpholino subunits with phosphorus-containing intersubunit linkages, designed to hybridize with dystrophin pre-mRNA and induce exon skipping
Data Source
AI summary
Provided are antisense molecules capable of binding to a selected target site in the human dystrophin gene to induce exon skipping, and methods of use thereof to treat muscular dystrophy.