Modified Nucleic Acid Duplexes for Stable Gene Silencing
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Solution Overview
Problem
Existing nucleic acid compounds for gene silencing in therapeutic applications face challenges in efficacy and stability, particularly in targeting specific diseases such as central-nervous-system diseases, inflammatory diseases, metabolic disorders, oncology, infectious diseases, and ocular diseases.
Innovation Solution
Development of nucleic acid compounds with specific 2′ sugar modifications, phosphorothioate internucleoside linkages, and abasic nucleosides in duplex regions to enhance target gene inhibition, including 2′-F, 2′-Me, and thermally destabilizing modifications, with inverted abasic nucleosides at the 3′ terminus for improved specificity and stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional nucleic acid compounds are used for gene silencing, then therapeutic applications are achieved, but efficacy and stability are insufficient
Solution Approach 1:
The patent applies parameter changes by modifying the sugar moiety at the 2' position of nucleosides in the nucleic acid compound. Specifically, it uses a mixture of 2'-F and 2'-Me sugar modifications, which changes the physical and chemical properties of the nucleic acid to enhance both stability and gene silencing efficacy. This chemical modification allows the compound to resist degradation while maintaining or improving its ability to silence target genes.
Solution Approach 2:
The patent employs composite materials by combining different sugar modifications (2'-F and 2'-Me) within the same nucleic acid compound structure. This composite approach allows the molecule to simultaneously achieve enhanced stability from one modification and improved silencing efficacy from another, resolving the contradiction between stability and efficacy that plagues conventional single-modification compounds.
2Stability of the object's composition
If nucleic acid compounds are modified to enhance stability, then compound stability improves, but gene silencing efficacy may be compromised
Solution Approach 1:
The patent uses parameter changes by strategically selecting and positioning specific sugar modifications (2'-F and 2'-Me) at particular locations within the nucleic acid sequence. This localized modification approach ensures that stability-enhancing modifications are placed where they provide maximum protection without interfering with the critical gene silencing function, thus maintaining efficacy while improving stability.
Solution Approach 2:
The patent applies local quality by making different parts of the nucleic acid compound have different properties. Specifically, it uses a mixture of 2'-F and 2'-Me modifications at different positions along the sequence, creating regions of enhanced stability that do not compromise the overall silencing capability. This localized differentiation allows the molecule to simultaneously achieve both stability and efficacy.
3Productivity
If conventional nucleic acid compounds are used, then simplicity of structure is maintained, but therapeutic effectiveness is limited
Solution Approach 1:
The patent applies parameter changes by introducing specific chemical modifications (2'-F and 2'-Me sugar moieties) to enhance therapeutic effectiveness. These parameter changes in the molecular structure enable the compound to achieve superior gene silencing efficacy and stability compared to conventional unmodified nucleic acid compounds, directly improving therapeutic productivity.
Solution Approach 2:
The patent uses composite materials by combining multiple sugar modifications within the nucleic acid structure to achieve enhanced therapeutic effectiveness. This composite approach allows the compound to simultaneously improve stability, efficacy, and half-life, thereby increasing productivity without requiring entirely new structural paradigms.
Data Source
AI summary
The present invention provides novel nucleic acid compounds suitable for therapeutic use. Additionally, the present invention provides methods of making these compounds, as well as methods of using such compounds for the treatment of various diseases and conditions.