Factor XI Oligomeric Compounds for Selective Silencing
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Solution Overview
Problem
Current anticoagulant therapies for thromboembolic diseases, such as warfarin, heparin, and direct oral anticoagulants, pose risks of increased bleeding and require careful monitoring, while RNA interference methods for gene silencing have limitations in identifying potent siRNAs with minimal off-target effects.
Innovation Solution
Development of oligomeric compounds that modulate and inhibit Factor XI gene expression through RNA interference, utilizing specific nucleobase sequences to target and degrade FXI mRNA, thereby reducing protein production and minimizing bleeding risks.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional anticoagulants (warfarin, heparin, DOACs) are used to treat thromboembolic diseases, then thromboembolic risk is reduced, but bleeding risk increases and requires careful monitoring
Solution Approach 1:
The patent extracts and selectively targets Factor XI, a specific coagulation factor, for inhibition using oligomeric compounds. By focusing on FXI rather than broadly inhibiting multiple coagulation factors, the therapy achieves thromboembolic protection while sparing other coagulation pathways, thereby reducing bleeding risk compared to conventional anticoagulants that inhibit multiple factors including those essential for hemostasis.
Solution Approach 2:
The invention applies local quality by designing oligomeric compounds with specific nucleobase sequences that target FXI mRNA in a sequence-specific manner. This localized molecular targeting allows inhibition of FXI expression without affecting other coagulation factors, achieving selective action that reduces bleeding complications while maintaining thromboembolic protection.
2Reliability
If RNA interference methods are used to silence Factor XI gene expression, then FXI protein production is reduced, but identifying potent siRNAs with minimal off-target effects becomes difficult
Solution Approach 1:
The patent changes the fundamental parameter of RNA interference from short interfering RNAs (siRNAs) to oligomeric compounds with specific nucleobase sequences. This parameter change enables more precise and predictable targeting of FXI mRNA, improving the ability to identify potent compounds with minimal off-target effects through systematic evaluation of sequence specificity and binding characteristics.
Solution Approach 2:
The invention segments the RNA silencing approach by using discrete oligomeric compounds with defined nucleobase sequences rather than relying on complex siRNA mechanisms. This segmentation allows for systematic design and evaluation of individual compounds with specific target sequences, making it easier to assess potency and off-target effects through controlled experimentation and sequencing analysis.
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 oligomeric compounds effectively inhibit FXI gene expression, providing a therapeutic approach for thromboembolic diseases with reduced bleeding risks and improved safety profiles.
Implementation Method 1
Nucleic acid products are provided that modulate, interfere with, or inhibit, Factor XI (FXI) gene expression. Methods, compounds, and compositions are provided for reducing expression of FXI mRNA and protein in an animal.
Implementation Method 2
The compound comprises at least a first region of linked nucleosides having at least a first nucleobase sequence that is at least partially complementary to at least a portion of RNA transcribed from an FXI gene
Data Source
AI summary
Products, compositions, and their uses are provided. In particular, nucleic acid products that modulate, in particular interfere with or inhibit, Factor XI (FXI) gene expression are provided. The products can be oligomeric compounds that comprise at least a first region of linked nucleosides having at least a first nucleobase sequence that is at least partially complementary to at least a portion of RNA transcribed from an FXI gene, wherein said first nucleobase sequence is selected from the following sequences, or a portion thereof: SEQ ID NOs 1 to 250.