Oligonucleotide Conjugates for Correcting Mis-Spliced mRNA
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Solution Overview
Problem
Current therapies fail to effectively modulate RNA processing to correct incorrectly spliced mRNA transcripts, leading to diseases such as muscular dystrophy and cancer, by inducing exon skipping or inclusion to produce functional proteins.
Innovation Solution
Administering polynucleic acid molecule conjugates, conjugated to a cell-targeting binding moiety, that induce insertion, deletion, or alteration in incorrectly spliced mRNA transcripts to generate fully processed mRNA transcripts encoding functional proteins, using 2′ modified nucleotides, modified internucleotide linkages, or inverted abasic moieties.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional oligonucleotide therapies are used to modulate RNA processing, then some RNA function modulation is achieved, but they fail to effectively correct incorrectly spliced mRNA transcripts
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure of oligonucleotides through 2′ modifications (such as 2′-O-methyl, 2′-O-methoxyethyl) and modified internucleotide linkages (such as phosphorothioate). These chemical parameter changes enhance the ability of oligonucleotides to induce exon skipping or inclusion, thereby effectively correcting incorrectly spliced mRNA transcripts while maintaining target specificity.
2Reliability
If oligonucleotide therapeutics are administered to modulate protein expression, then disease treatment is achieved, but delivery to specific cells remains insufficient
Solution Approach 1:
The patent employs cell-penetrating peptides as intermediary molecules that facilitate the delivery of oligonucleotide therapeutics into specific cells. The conjugation of cell-penetrating peptides to oligonucleotides creates a mediator system that overcomes cellular uptake barriers, enabling effective delivery of the therapeutic agent to the target cells while maintaining the oligonucleotide's RNA modulation function.
3Ease of manufacture
If standard nucleotide sequences are used in oligonucleotide therapeutics, then synthesis is simplified, but stability and efficacy are reduced
Solution Approach 1:
The patent applies local quality by implementing modifications at specific positions within the oligonucleotide sequence rather than uniformly throughout. For example, 2′ modifications are applied at particular nucleotide positions where they provide maximum stability and efficacy enhancement, while unmodified positions are retained to maintain ease of synthesis and appropriate flexibility. This localized modification strategy optimizes both manufacturability and therapeutic performance.
Data Source
AI summary
Disclosed herein are molecules and pharmaceutical compositions that induce an insertion, deletion, duplication, or alteration in an incorrectly spliced mRNA transcript to induce exon skipping or exon inclusion. Also described herein include methods for treating a disease or disorder that comprises a molecule or a pharmaceutical composition that induces an insertion, deletion, duplication, or alteration in an incorrectly spliced mRNA transcript to induce exon skipping or exon inclusion.