Abasic Nucleotide RNA Duplexes for Sustained Gene Silencing
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Solution Overview
Problem
Current oligonucleotide compounds for therapeutic gene silencing face challenges in effectively targeting and inhibiting specific gene expression in cells, particularly in achieving sustained suppression of target genes in tissues like the liver.
Innovation Solution
Development of nucleic acid compounds, specifically RNA molecules with abasic nucleotides and reversed internucleotide linkages, that form duplex structures with complementary strands to inhibit gene expression, and conjugates with ligand moieties for enhanced cellular uptake and distribution.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of moving object
If traditional oligonucleotide compounds are used for gene silencing, then gene expression inhibition is achieved, but the duration of action is insufficient and sustained suppression is not maintained
Solution Approach 1:
The patent modifies the chemical parameters of oligonucleotide compounds by incorporating abasic nucleotides and reversed internucleotide linkages, which fundamentally changes the molecular structure and properties. This enables sustained suppression of target gene expression in liver tissues, resolving the contradiction between duration of action and reliability of gene silencing efficacy
Solution Approach 2:
The invention creates composite oligonucleotide structures by combining abasic nucleotides with reversed linkages and conjugating them to ligand moieties. This composite approach enhances both the duration and reliability of gene silencing, allowing sustained therapeutic effects in difficult-to-treat tissues like the liver
2Measurement precision
If oligonucleotide compounds are designed for specific gene targeting, then gene silencing specificity is improved, but the compounds fail to achieve effective distribution and uptake in target tissues
Solution Approach 1:
The patent introduces ligand moieties as intermediary components that facilitate the interaction between oligonucleotide compounds and target cells. These ligands act as mediators that enhance cellular uptake and tissue distribution while maintaining the specific gene-targeting capability of the oligonucleotide sequence, thereby resolving the contradiction between targeting precision and delivery efficiency
3Ease of manufacture
If conventional oligonucleotide structures are used, then synthesis is relatively simple, but therapeutic efficacy in treating diseases is insufficient
Solution Approach 1:
The patent implements parameter changes in the oligonucleotide structure by incorporating abasic nucleotides and reversed linkages, which enhance therapeutic efficacy while maintaining feasibility of synthesis. The modified structures provide improved stability and activity, resolving the contradiction between manufacturing simplicity and therapeutic effectiveness
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
These compounds demonstrate effective and sustained suppression of target gene expression in both cancer cells and primary human hepatocytes, showing promise for therapeutic applications by reducing mRNA levels and maintaining efficacy over extended periods.
Implementation Method 1
comprising at least one duplex region that comprises at least a portion of a first strand and at least a portion of a second strand that is at least partially complementary to the first strand
Data Source
AI summary
The present invention relates to nucleic acid molecules for use in the treatment or prevention of disease.