Modified Nucleic Acid Duplexes for Stable, Specific Gene Silencing
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Solution Overview
Problem
Current gene-silencing agents, such as siRNA and micro-RNA, face challenges in effectively inhibiting protein formation for various diseases due to limitations in thermal stability and specificity, particularly in therapeutic applications.
Innovation Solution
Development of nucleic acid compounds with specific structural modifications, including 2′ sugar and abasic nucleoside patterns, thermally destabilizing modifications, and phosphorothioate linkages, to enhance thermal stability and target gene inhibition.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional siRNA and micro-RNA are used for gene silencing, then gene expression inhibition is achieved, but thermal stability and specificity are insufficient for effective therapeutic application
Solution Approach 1:
The patent applies parameter changes by introducing thermally destabilizing modifications at specific positions (first 9 nucleoside positions of the 5' region) of the nucleic acid duplex. These modifications selectively alter the thermal properties of the duplex to enhance specificity and reduce off-target effects, while maintaining overall thermal stability through the modified sugar patterns (2' Me and 2' F) and phosphorothioate linkages throughout the molecule.
Solution Approach 2:
The patent implements local quality by placing different modifications at different locations within the nucleic acid structure. Specifically, thermally destabilizing modifications are concentrated in the 5' region (first 9 nucleoside positions) to control initiation and specificity, while modified sugar patterns and phosphorothioate linkages are distributed throughout the duplex to maintain structural stability and protect against degradation.
2Measurement precision
If conventional siRNA compounds are used, then gene silencing is achieved, but specificity and thermal stability are limited
Solution Approach 1:
The patent uses parameter changes by introducing thermally destabilizing modifications at specific positions (first 9 nucleoside positions of the 5' region) of the nucleic acid duplex. These modifications selectively alter the thermal properties of the duplex to enhance specificity and reduce off-target effects, while maintaining overall thermal stability through the modified sugar patterns (2' Me and 2' F) and phosphorothioate linkages throughout the molecule.
Solution Approach 2:
The patent implements local quality by placing different modifications at different locations within the nucleic acid structure. Specifically, thermally destabilizing modifications are concentrated in the 5' region (first 9 nucleoside positions) to control initiation and specificity, while modified sugar patterns and phosphorothioate linkages are distributed throughout the duplex to maintain structural stability and protect against degradation.
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 modified nucleic acid compounds demonstrate improved thermal stability and specificity, leading to enhanced gene silencing efficacy for treating diseases like haemophilia, diabetes, and cardiovascular diseases.
Implementation Method 1
said first strand comprises at least one thermally destabilizing modification of the duplex within the first 9 nucleoside positions of the 5' region thereof
Implementation Method 2
said penultimate abasic nucleoside is connected to an adjacent first basic nucleoside in an adjacent 5' near terminal region through a reversed internucleoside linkage; the reversed linkage is a 5-5' reversed linkage
Implementation Method 3
the second strand comprises 2 consecutive abasic nucleosides in the 5' terminal region of the second strand
Implementation Method 4
phosphorothioate linkages
Implementation Method 5
nucleosides of said first strand comprise a 2' sugar modification pattern wherein said modifications are selected at least from 2' Me and 2' F sugar modifications
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.