Phosphorodithioate Nucleic Acids for Nuclease Resistance
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Solution Overview
Problem
The delivery of nucleic acids, particularly double-stranded siRNAs, to cells in vivo is challenging due to degradation by cellular nucleases and the need for specific targeting, with existing targeting ligands often failing to translate to in vivo settings, necessitating improved receptor-specific ligand conjugated iRNA duplex agents and methods for their preparation.
Innovation Solution
A nucleic acid with phosphorodithioate linkages between nucleotides, optionally conjugated with ligands like N-acetyl galactosamine, is developed to enhance stability and targeting, comprising a structure that includes a duplex region with complementary strands and specific modifications to resist degradation and improve cellular uptake.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If nucleic acids are delivered to cells in vivo, then gene expression inhibition is achieved, but degradation by cellular nucleases occurs
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure of the nucleic acid backbone, specifically replacing phosphodiester linkages with phosphorodithioate linkages. This chemical parameter change increases resistance to nuclease degradation while maintaining the gene-silencing function, thereby resolving the contradiction between efficacy and stability.
Solution Approach 2:
The patent employs composite materials by combining modified nucleotide building blocks with phosphorodithioate linkages to create a hybrid nucleic acid structure. This composite approach integrates the stability of modified chemical linkages with the functional properties of RNA sequences, achieving both nuclease resistance and gene expression inhibition.
2Measurement precision
If targeting ligands are conjugated to iRNA duplex agents, then specific targeting is improved, but translation to in vivo settings is poor
Solution Approach 1:
The patent applies parameter changes by modifying the chemical properties of the nucleic acid backbone through phosphorodithioate linkages, which alter the molecule's stability and interaction characteristics. This chemical modification improves in vivo performance while maintaining targeting capability, addressing the translation problem between in vitro and in vivo settings.
Data Source
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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.