Inverted Nucleotide iRNA Duplex Stability
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Solution Overview
Problem
The delivery of nucleic acids, such as RNA, to cells in vivo is challenging due to degradation by cellular nucleases and the need for specific targeting, with existing methods not always translating effectively to in vivo settings, and there is a need for more efficacious receptor-specific ligand-conjugated iRNA duplex agents for therapeutic use.
Innovation Solution
A nucleic acid with increased stability is developed, featuring a duplex region with inverted nucleotides attached via 3' or 5' carbon atoms and modified phosphodiester linkages, conjugated with ligands like N-acetyl galactosamine moieties for targeted delivery, enhancing stability and cellular uptake.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If nucleic acids are delivered to cells in vivo, then gene inhibition efficacy is achieved, but degradation by cellular nucleases occurs reducing stability
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure of nucleic acids through inverted nucleotides and modified phosphodiester linkages. These structural parameter changes increase resistance to nuclease degradation while maintaining gene silencing efficacy, directly resolving the contradiction between stability and duration of action
Solution Approach 2:
The patent employs composite materials by combining inverted nucleotides with modified phosphodiester linkages to create hybrid nucleic acid structures. This composite approach enhances overall stability and nuclease resistance beyond what single modifications could achieve alone
2Measurement precision
If targeting ligands are conjugated to iRNA duplex agents, then specific targeting is improved, but translation to in vivo settings remains insufficient
Solution Approach 1:
The patent modifies the chemical parameters of targeting ligands through inverted nucleotide configurations and phosphodiester modifications. These parameter changes enhance the in vivo performance of ligand-conjugated iRNA duplex agents by improving stability and cellular uptake efficiency
Solution Approach 2:
The patent uses modified phosphodiester linkages as intermediary structures that connect targeting ligands to the iRNA duplex core. These intermediary modifications facilitate better integration and performance of targeting moieties in the in vivo environment
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 nucleic acid achieves targeted gene inhibition with improved stability and reduced toxicity, effectively entering cells and maintaining efficacy while minimizing off-target effects.
Implementation Method 1
the terminal nucleotide at the 3′ end of at least one of the first strand and the second strand is an inverted nucleotide and is attached to the adjacent nucleotide via the 3′ carbon of the terminal nucleotide and the 3′ carbon of the adjacent nucleotide
Data Source
AI summary
The present invention relates to products and compositions and their uses. In particular the invention relates to nucleic acid products that interfere with target gene expression or inhibit target gene expression and therapeutic uses of such products.