Chirally Controlled DMD Oligonucleotides for Stable Exon Skipping
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Solution Overview
Problem
Existing oligonucleotides for treating muscular dystrophy, such as DMD, face challenges with instability, poor cell penetration, and distribution, as well as limited efficacy in modulating exon skipping and inducing immune responses.
Innovation Solution
Development of chirally controlled DMD oligonucleotides with specific chemical modifications and stereochemistry, including non-negatively charged internucleotidic linkages, to enhance exon skipping efficiency and reduce toxicity, thereby modulating DMD transcript splicing and producing internally truncated but partially functional dystrophin proteins.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If naturally occurring nucleic acids are used for therapeutics, then the treatment approach is simple and straightforward, but the oligonucleotides exhibit poor stability against nucleases and poor cell penetration
Solution Approach 1:
The patent applies composite materials by combining multiple chemical modifications (2'-O-methyl, phosphorothioate linkages, 5-methylcytosine) with naturally occurring nucleic acid structures to create DMD oligonucleotides that maintain sequence-specific binding while achieving enhanced stability and cellular uptake. This composite approach allows the oligonucleotide to function as both a therapeutic agent and a stable, cell-penetrating molecule.
Solution Approach 2:
The patent systematically changes chemical parameters of the oligonucleotide structure, including modifying the sugar moiety (2'-O-methyl), the internucleotidic linkage (phosphorothioate), and the base (5-methylcytosine). These parameter changes collectively improve nuclease resistance and cell penetration while preserving the ability to mediate exon skipping.
2Adaptability or versatility
If conventional oligonucleotides are used to modulate exon skipping, then the approach is established and familiar, but the efficacy is limited and immune responses are induced
Solution Approach 1:
The patent changes the chemical parameters of conventional oligonucleotides by introducing 2'-O-methyl modifications, phosphorothioate linkages, and 5-methylcytosine bases. These modifications reduce immune response by decreasing recognition by immune sensors while maintaining or enhancing exon skipping efficacy through improved stability and cellular delivery.
Solution Approach 2:
The patent converts the potential harm of immune recognition into a benefit by using phosphorothioate linkages and 5-methylcytosine modifications that reduce immune activation. These modifications transform the oligonucleotide from an immunogenic molecule into one that is better tolerated by the immune system while maintaining therapeutic function.
3Reliability
If oligonucleotides with chemical modifications are developed to improve stability, then the stability and cell penetration are enhanced, but the complexity of the oligonucleotide structure increases
Solution Approach 1:
The patent applies systematic parameter changes by modifying specific components of the oligonucleotide (sugar, linkage, base) rather than the entire structure. This modular approach to modification allows for improved stability and cell penetration while maintaining a relatively straightforward synthetic pathway and structure that can be manufactured using established oligonucleotide synthesis methods.
Data Source
AI summary
Among other things, the present disclosure provides designed DMD oligonucleotides, compositions, and methods of use thereof. In some embodiments, the present disclosure provides technologies useful for repairing mutant DMD transcripts by skipping exon 51 or exon 53, so that the transcript can be translated into an internally truncated but at least partially functional Dystrophin protein variant. In some embodiments, the present disclosure provides technologies useful for modulating DMD transcript splicing. In some embodiments, provided technologies can alter splicing of a dystrophin (DMD) DMD transcript. In some embodiments, the present disclosure provides methods for treating diseases, such as muscular dystrophy, including but not limited to Duchenne muscular dystrophy, Becker's muscular dystrophy, etc.