Modified Oligonucleotide Compositions for DMD Exon Skipping
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Solution Overview
Problem
Existing oligonucleotides face challenges such as instability against nucleases, poor cell penetration, and limited distribution, which hinder their therapeutic efficacy, particularly in modulating exon skipping for muscular dystrophy.
Innovation Solution
Development of oligonucleotide compositions with controlled structural elements, including chemical modifications and backbone stereochemistry, to enhance stability, reduce toxicity, and improve splicing efficacy, utilizing non-negatively charged internucleotidic linkages and chirally controlled configurations.
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 modified nucleic acid components (2'-O-methoxyethyl modifications, phosphorodithioate linkages, LNA units) into a single oligonucleotide structure. This composite approach creates an enhanced therapeutic agent that maintains the simplicity of nucleic acid-based therapy while achieving superior stability and cell penetration through the synergistic effects of different molecular modifications.
Solution Approach 2:
The patent implements parameter changes by systematically modifying key physical and chemical parameters of the oligonucleotide structure: sugar modifications (2'-O-methoxyethyl), linkage modifications (phosphorodithioate), and incorporating LNA units. These parameter changes transform the molecular properties to achieve both improved stability against nuclease degradation and enhanced cellular uptake, while preserving the therapeutic mechanism of action.
2Reliability
If oligonucleotides are modified to improve stability and cell penetration, then therapeutic efficacy is enhanced, but the structural complexity and manufacturing difficulty increase
Solution Approach 1:
The patent applies segmentation by dividing the oligonucleotide into distinct functional regions: 2'-O-methoxyethyl modified nucleotides for stability, phosphorodithioate linkages for nuclease resistance, and LNA units for enhanced binding affinity. This segmented design allows each component to perform its specific function while maintaining overall structural organization that facilitates manufacturing through standardized synthesis protocols.
Solution Approach 2:
The patent implements local quality by applying specific modifications at strategic positions within the oligonucleotide sequence. The 2'-O-methoxyethyl modifications, phosphorodithioate linkages, and LNA units are positioned at specific locations to optimize their individual contributions to stability and cell penetration while minimizing overall structural complexity and manufacturing burden.
3Ease of manufacture
If conventional oligonucleotide compositions are used, then manufacturing is straightforward, but the splicing efficacy and protein production are limited
Solution Approach 1:
The patent applies self-service by designing the oligonucleotide structure to inherently achieve enhanced splicing efficacy through its modified components. The 2'-O-methoxyethyl modifications, phosphorodithioate linkages, and LNA units work autonomously to improve nuclear uptake, binding affinity to the target pre-mRNA, and resistance to degradation, eliminating the need for additional delivery systems or complex manufacturing processes to achieve high productivity.
Data Source
AI summary
Among other things, the present disclosure provides designed oligonucleotides, compositions, and methods of use thereof. In some embodiments, the present disclosure provides technologies useful for reducing levels of transcripts. In some embodiments, the present disclosure provides technologies useful for modulating transcript splicing. In some embodiments, provided technologies can alter splicing of a dystrophin (DMD) transcript. In some embodiments, the present disclosure provides methods for treating diseases, such as Duchenne muscular dystrophy, Becker's muscular dystrophy, etc.