Repeat-Targeting Oligonucleotides for Selective RNA Splicing Modulation
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Solution Overview
Problem
Certain diseases, such as atrophin 1 (DRPLA), Huntington's Disease, and spinocerebellar ataxias, are caused by expanded repeat-containing RNA molecules that disrupt cellular function, and existing oligonucleotides are inadequate in modulating the splicing of these RNAs effectively.
Innovation Solution
A single-stranded oligonucleotide with specific nucleobase sequences complementary to expanded CAG repeat regions in target RNA, comprising 13 to 30 linked nucleosides, is used to modulate splicing by including a hybridizing region with up to three mismatches and a phosphate moiety, and incorporating RNA-like nucleosides and sugar motifs for enhanced targeting and stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing oligonucleotides are used to target expanded repeat regions, then some splicing modulation effect is achieved, but the effectiveness and selectivity are inadequate
Solution Approach 1:
The patent applies local quality by creating a hybridizing region with specific local characteristics (up to three mismatches allowed) that differ from perfect complementarity. This localized tolerance in the repeat region allows the oligonucleotide to selectively bind expanded repeats while maintaining overall targeting precision through the rest of the sequence.
Solution Approach 2:
The patent changes the parameter of complementarity strictness by allowing up to three mismatches in the hybridizing region. This parameter modification enables the oligonucleotide to effectively target expanded repeat regions while maintaining sufficient specificity through controlled imperfection in the binding region.
2Reliability
If standard oligonucleotide structures are used, then basic targeting is achieved, but stability and affinity for target sites are insufficient
Solution Approach 1:
The patent uses composite materials by incorporating multiple types of modified nucleosides (2'-F, 2'-MOE, 2'-OMe, LNA, F-HNA, cEt) and various sugar motifs into a single oligonucleotide structure. This composite approach combines different stabilizing and affinity-enhancing elements to achieve both high targeting affinity and molecular stability.
Solution Approach 2:
The patent changes the chemical parameters of the oligonucleotide by incorporating non-natural nucleosides and sugar motifs that alter the structural and chemical properties. These parameter changes enhance both the stability of the oligonucleotide molecule and its affinity for target sites through optimized binding interactions.
3Measurement precision
If the oligonucleotide sequence is extended to improve targeting, then selectivity increases, but the complexity of the molecule increases
Solution Approach 1:
The patent applies segmentation by dividing the oligonucleotide into distinct functional regions: a 5' terminal region with phosphate moiety and specific nucleoside, a hybridizing region with controlled mismatches for target binding, and a 3' terminal region with specific nucleosides. This segmented structure achieves high selectivity through functional specialization without unnecessary complexity.
Solution Approach 2:
The patent uses local quality by concentrating specific modifications and features only where needed: the phosphate moiety and specific nucleosides are placed at the 5' end for stability and binding initiation, while the hybridizing region with controlled mismatches is positioned for optimal target interaction. This localized optimization achieves high selectivity without uniformly increasing molecular complexity throughout the entire sequence.
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
The oligonucleotide effectively modulates splicing of expanded repeat-containing RNA, reducing the disruptive effects and potentially treating associated diseases by stabilizing the 5'-phosphate moiety and enhancing selectivity and affinity for target sites.
Implementation Method 1
the oligonucleotide comprises a hybridizing region and 0-4 3'-terminal nucleosides, and wherein the hybridizing region is 100% complementary to the repeat region of the expanded repeat-containing target RNA
Data Source
Figure 1
Figure 2A~2B
Figure 3a
AI summary
Described are compounds and methods useful for the treatment and investigation of diseases and disorders associated with expanded repeat-containing RNA molecules. In certain embodiments, compounds and methods useful for the modulation of ATXN-3 pre-mRNA are described. In certain embodiments, compounds and methods useful for the modulation of ATN-1 mRNA are described.