dsRNA Molecules for Selective Factor V Leiden Gene Silencing
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Solution Overview
Problem
Current treatments for Factor V Leiden thrombophilia lack an agent that can selectively and efficiently silence the Factor V Leiden mutant gene using the cell's own RNA interference machinery, offering high biological activity and in vivo stability to effectively inhibit the expression of the target gene.
Innovation Solution
Development of double-stranded ribonucleic acid (dsRNA) molecules that are complementary to the mRNA transcript of the Factor V Leiden mutant gene, specifically designed to inhibit gene expression by targeting and degrading the mRNA through RNA interference, with modifications such as 2′-O-methyl nucleotides and terminal nucleotide conjugations for enhanced stability and activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional treatments are used for Factor V Leiden thrombophilia, then the treatment can be administered, but they cannot selectively and efficiently silence the Factor V Leiden mutant gene
Solution Approach 1:
The patent applies local quality by designing dsRNA molecules with specific sequence complementarity that targets only the Factor V Leiden mutant mRNA. The antisense strand is engineered to match the mutant sequence (particularly the G1691A mutation region), ensuring selective binding and silencing of the mutant gene while sparing the wild-type allele, thus achieving both selectivity and efficiency
Solution Approach 2:
The patent employs parameter changes by modifying the dsRNA structure with 2′-O-methyl nucleotide modifications and terminal conjugations. These chemical modifications enhance the stability and biological activity of the dsRNA molecule, improving its ability to efficiently silence the target gene while maintaining selectivity
2Reliability
If dsRNA molecules are designed to inhibit Factor V Leiden gene expression, then gene silencing efficiency is improved, but in vivo stability may be compromised
Solution Approach 1:
The patent resolves this contradiction by chemically modifying the dsRNA structure. The 2′-O-methyl nucleotide modifications and terminal conjugations (such as cholesterol or other stabilizing groups) increase the molecular stability and resistance to nucleases in vivo, while preserving the ability to effectively silence the target gene expression
3Reliability
If high dosages are used to achieve effective gene silencing, then therapeutic effect is improved, but stability and side effects worsen
Solution Approach 1:
The patent addresses this contradiction through chemical modifications of the dsRNA molecule. The 2′-O-methyl and terminal conjugation modifications enhance the drug's stability and pharmacokinetic properties, allowing effective gene silencing at lower dosages while reducing the risk of side effects and improving overall therapeutic index
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 dsRNA molecules achieve significant inhibition of the Factor V Leiden mutant gene expression, providing a therapeutic approach for treating thrombophilia with low dosages and improved stability, effectively reducing the risk of venous thrombosis and associated complications.
Implementation Method 1
double-stranded ribonucleic acid (dsRNA), and its use in mediating RNA interference to inhibit the expression of the Factor V Leiden mutant gene
Data Source
AI summary
The invention relates to a double-stranded ribonucleic acid (dsRNA) for inhibiting the expression of Factor V, comprising an antisense strand having a nucleotide sequence which is less that 25 nucleotides in length and which is substantially complementary to at least a part of Factor V. The invention also relates to a pharmaceutical composition comprising the dsRNA together with a pharmaceutically acceptable carrier; methods for treating diseases caused by the expression of Factor V using the pharmaceutical composition; and methods for inhibiting the expression of Factor V in a cell.