Oligomeric Compounds Modulating Pre-mRNA Splicing
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Solution Overview
Problem
Current technologies face challenges in effectively modulating splicing of pre-mRNA to address aberrant splicing caused by point mutations, which can lead to genetic diseases.
Innovation Solution
Development of oligomeric compounds with specific internucleoside linkage motifs, such as phosphorothioate and phosphodiester linkages, to target and modulate splicing of selected pre-mRNA molecules.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If antisense oligonucleotides are used to target aberrant splice sites, then splicing modulation activity is achieved, but tolerability and safety are compromised
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure of oligonucleotide linkages from traditional phosphodiester to phosphorothioate and methylphosphonate types. This structural parameter change enhances splicing modulation activity while simultaneously improving tolerability by reducing off-target effects and immune stimulation, directly resolving the technical contradiction between activity and safety
Solution Approach 2:
The patent employs composite materials by creating hybrid oligomeric compounds that combine different linkage types (phosphorothioate and methylphosphonate) within the same molecule. This composite approach allows optimization of both activity and tolerability by leveraging the complementary properties of each linkage type, achieving superior risk-benefit profile compared to homogeneous structures
2Reliability
If point mutations are present in pre-mRNA, then aberrant splicing occurs leading to genetic diseases, but the ability to selectively target and correct these mutations is limited
Solution Approach 1:
The patent applies local quality by designing oligomeric compounds with specific sequence complementarity that targets only the aberrant splice site created by the point mutation. The modified linkage structures enhance local binding affinity and specificity at the mutation site, allowing selective correction of the aberrant splicing without affecting normal splicing events elsewhere in the genome
Solution Approach 2:
The patent uses parameter changes in the form of modified nucleotide analogs and linkage structures that enhance discrimination between mutant and wild-type sequences. These chemical parameter modifications improve the selectivity of the oligomeric compounds for aberrant splice sites, enabling precise targeting of disease-causing mutations while preserving normal splicing function
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 oligomeric compounds improve the tolerability and activity of splicing modulation, effectively addressing aberrant splicing and ameliorating symptoms of associated diseases.
Implementation Method 1
The principle behind antisense technology is that an antisense compound, which hybridizes to a target nucleic acid, modulates activities such as transcription, splicing or translation
Implementation Method 2
oligomeric compounds have phosphorothioate internucleoside linkages and phosphodiester internucleoside linkages
Data Source
AI summary
Provided are compounds, methods, and pharmaceutical compositions for modulating splicing of a pre-mRNA in a cell or subject. Such compounds, methods, and pharmaceutical compositions are useful to ameliorate at least one symptom of a disease or disorder.