Modified dsRNA Nucleosides for Stable Gene Silencing Specificity
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Solution Overview
Problem
Current RNAi-targeted drugs face challenges such as poor stability, weak gene silencing effect, and off-target effects due to unmodified siRNA, which limits their clinical application and effectiveness in treating diseases.
Innovation Solution
A modified nucleoside monomer is incorporated into the structure of double-stranded ribonucleic acid (dsRNA) to enhance specific binding and minimize non-specific binding, thereby reducing off-target effects while maintaining gene silencing efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If unmodified siRNA is used for RNAi therapy, then the structure is simple and easy to manufacture, but the stability is poor and gene silencing effect is weak
Solution Approach 1:
The patent applies composite materials by incorporating modified nucleosides (such as 2'-O-methyl, 2'-fluoro, or locked nucleic acid modifications) into the siRNA structure. These modified nucleosides create a composite RNA molecule that combines the natural RNA backbone with chemically modified units, thereby enhancing stability against nucleases and improving gene silencing efficacy while maintaining manufacturability through established chemical synthesis methods
Solution Approach 2:
The patent employs parameter changes by modifying chemical parameters of the nucleoside structure, specifically altering the sugar moiety (2'-position modifications) and base composition. These parameter changes in the molecular structure enhance the physical and chemical properties of siRNA, including increased resistance to degradation and improved binding affinity to target mRNA, thus resolving the stability issue
2Ease of manufacture
If unmodified siRNA is used for RNAi therapy, then the manufacturing process is simple, but the gene silencing effect is weak
Solution Approach 1:
The patent uses composite materials by integrating modified nucleoside units into the siRNA sequence. These modified units (e.g., LNA, 2'-O-Me) create a composite structure that enhances binding affinity to target mRNA through increased rigidity and pre-organization of the RNA helix, thereby significantly improving gene silencing efficacy while remaining compatible with standard solid-phase synthesis protocols
3Device complexity
If standard siRNA is used, then the structure is simple, but off-target effects occur
Solution Approach 1:
The patent applies local quality by introducing modifications specifically at the 2'-position of ribose in certain nucleotides of the siRNA sequence, while leaving other positions unmodified. This localized modification strategy enhances specificity of target binding at critical positions (such as the seed region) without overly complicating the overall structure, thereby reducing off-target effects through improved discrimination against mismatched sequences
4Adaptability or versatility
If siRNA is administered systemically, then the treatment coverage is broad, but the phosphodiester bond is vulnerable to degradation by nucleases
Solution Approach 1:
The patent employs composite materials by incorporating chemically modified nucleoside units throughout the siRNA sequence that are resistant to nuclease degradation. These modified units create a composite structure where the altered sugar-phosphate backbone provides enhanced stability against enzymatic cleavage, enabling systemic administration and broad treatment coverage while maintaining structural integrity in circulation
Data Source
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AI summary
The present disclosure relates to the field of biomedicine, and in particular to a modified nucleoside monomer compound, a double-stranded ribonucleic acid containing same with reduced off-target effects or improved activity of inhibiting gene expression, and use for manufacturing a medicament for inhibiting target gene expression in mammalian cells and a composition comprising the medicament.