Modified FXI siRNA Conjugates for Stable Liver Gene Silencing
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Solution Overview
Problem
Current technologies face challenges in effectively inhibiting the expression of the Plasma Coagulation Factor XI (FXI) gene to prevent and treat thrombotic diseases such as venous thrombosis and ischemic stroke, particularly in targeting the liver for specific gene silencing.
Innovation Solution
Development of specific siRNAs with modified sequences that can form double-stranded regions with their complementary antisense strands, designed to target and inhibit the FXI gene expression in the liver, formulated into pharmaceutical compositions or conjugates for effective delivery.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional siRNA delivery systems are used, then the siRNA can be delivered to target cells, but the stability of siRNA is poor and off-target effects occur
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure of siRNA molecules through various nucleotide modifications (2'-O-methyl, phosphorothioate linkages, locked nucleic acids) to enhance stability and reduce off-target effects while maintaining target specificity
Solution Approach 2:
The patent employs composite materials by combining modified nucleotides with conjugating groups (such as cholesterol, cell-penetrating peptides, and liver-targeting ligands) to create enhanced siRNA conjugates that improve delivery efficiency, stability, and target specificity
2Quantity of substance
If non-specific siRNA sequences are used, then delivery to liver can be achieved, but the inhibitory activity against FXI gene is insufficient
Solution Approach 1:
The patent applies local quality by designing specific siRNA sequences (sense and antisense strands with complementary regions) that are precisely matched to the FXI gene target sequence, ensuring high specificity and inhibitory activity while minimizing off-target effects
3Productivity
If siRNA is administered without conjugation, then the administration process is simple, but the delivery efficiency to liver is low
Solution Approach 1:
The patent employs intermediaries by introducing conjugating groups (such as cell-penetrating peptides and liver-targeting ligands) that mediate the delivery of siRNA to hepatocytes, enhancing cellular uptake and liver-specific delivery efficiency
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 siRNAs demonstrate high stability, low off-target effects, and significant inhibitory activity against FXI mRNA, effectively treating and preventing thrombotic diseases by reducing FXI gene expression, with inhibition rates up to 95% in vivo.
Implementation Method 1
Based on the mechanism of RNA interference (RNAi), small interfering RNA (siRNA) could inhibit or block the expression of any target gene of interest in a sequence-specific manner
Implementation Method 2
the nucleotide sequence I and the nucleotide sequence II are at least partly reverse complementary to form a double-stranded region
Data Source
AI summary
Provided are an siRNA which inhibits plasma coagulation factor XI gene expression, a pharmaceutical composition containing the siRNA, a conjugate, a reagent kit, and a use of the siRNA, the pharmaceutical composition thereof and the conjugate in preparing a drug used for treating and/or preventing thrombotic diseases and ischemic strokes.