Modified Oligonucleotides for Nonsense Mediated Decay Splicing Correction
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Solution Overview
Problem
Current methods for addressing aberrant pre-mRNA processing, such as point mutations leading to aberrant splicing in genetic diseases, are limited in their ability to effectively modulate gene expression and correct splicing errors.
Innovation Solution
The use of modified oligomeric compounds comprising complementary nucleobase sequences that contact cells to reduce the activity or amount of target nucleic acid transcripts through nonsense mediated decay, specifically designed to alter splicing patterns by increasing or decreasing exon inclusion and introducing premature termination codons.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If antisense oligonucleotides are used to target mutations leading to aberrant splicing, then splicing can be redirected to give desired splice products, but the ability to effectively modulate gene expression and correct splicing errors is limited
Solution Approach 1:
The patent modifies the chemical structure of oligonucleotides by incorporating 2'-O-methoxyethyl (2'-MOE) sugar modifications and phosphorothioate backbone modifications. These parameter changes in the oligonucleotide structure enhance both the reliability of splicing correction and the versatility of gene expression modulation, resolving the contradiction between these two features.
Solution Approach 2:
The invention creates composite oligonucleotide structures combining multiple modified nucleosides (2'-MOE, phosphorothioate linkages) within a single molecule. This composite approach enables simultaneous achievement of reliable splicing correction and broad gene expression modulation capabilities, addressing the limitation of prior art.
2Reliability
If modified oligomeric compounds are designed to alter splicing patterns by introducing premature termination codons, then aberrant splicing can be reduced, but the complexity of the compound increases
Solution Approach 1:
The oligonucleotide is divided into functional segments: 2'-MOE modified nucleosides for high-affinity target binding and splicing modulation, phosphorothioate linkage segments for enhanced stability, and strategically positioned sequences that introduce premature termination codons. This segmentation allows reliable aberrant splicing reduction while managing structural complexity through modular design.
Solution Approach 2:
Different regions of the oligonucleotide possess different qualities: some nucleosides are 2'-MOE modified for binding affinity, others contain phosphorothioate linkages for stability, and specific positions are designed to create premature termination codons. This local differentiation achieves reliable splicing correction without requiring uniform complexity throughout the entire molecule.
3Adaptability or versatility
If antisense compounds are used to modulate gene expression activities, then specific gene products can be selectively targeted, but the effectiveness in combating aberrant pre-mRNA processing is limited
Solution Approach 1:
The patent applies 2'-MOE sugar modifications and phosphorothioate backbone modifications to antisense compounds, changing their physical and chemical parameters. These changes enhance both the versatility of gene expression modulation and the reliability of correcting aberrant pre-mRNA processing, simultaneously improving both features rather than trading one for the other.
Solution Approach 2:
The modified oligonucleotides act as intermediaries that bridge the gap between antisense compound binding and effective pre-mRNA processing correction. The 2'-MOE and phosphorothioate modifications enhance the intermediary function by improving binding affinity, stability, and cellular uptake, thereby increasing both versatility and reliability of the correction process.
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
This approach effectively modulates gene expression by reducing aberrant splicing and protein production, offering a therapeutic and diagnostic tool for genetic diseases by specifically targeting and degrading aberrant mRNA transcripts.
Implementation Method 1
an oligomeric compound comprising a modified oligonucleotide complementary to a nucleic acid transcript
Data Source
AI summary
Disclosed herein are compounds, compositions and methods for modulating the amount or activity of a target nucleic acid. In certain embodiments, the amount or activity of a target nucleic acid is modulated through nonsense mediated decay.