Modified Nucleic Acid Targeted Delivery
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
The delivery of nucleic acids, such as RNA, to cells while avoiding degradation by cellular nucleases and maintaining efficacy and target specificity has proven challenging for therapeutic use.
Innovation Solution
A nucleic acid comprising at least one duplex region with modified nucleotides at specific positions to facilitate processing by the RNA-induced silencing complex (RISC), and conjugated to a ligand for targeted delivery.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If nucleic acid is delivered to cells using conventional methods, then gene silencing efficacy can be achieved, but the nucleic acid is degraded by cellular nucleases and fails to maintain stability
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure of nucleic acid molecules through various modifications including 2'-O-methyl modifications, phosphorothioate backbone modifications, and 5'-methoxy modifications. These chemical parameter changes enhance nuclease resistance while maintaining or improving gene silencing efficacy, directly resolving the contradiction between stability and efficacy
Solution Approach 2:
The patent employs composite materials by combining modified nucleic acid sequences with delivery vehicles such as lipid nanoparticles and conjugating them with targeting ligands. This composite approach protects the nucleic acid from degradation while enabling targeted delivery and maintaining gene silencing activity, simultaneously addressing both stability and efficacy requirements
2Measurement precision
If targeting ligands are conjugated to nucleic acid for specific targeting, then target site delivery is improved, but the complexity of the delivery system increases
Solution Approach 1:
The patent applies universality by designing delivery systems that perform multiple functions simultaneously: the lipid nanoparticle provides both protection from nucleases and cellular uptake, while conjugated ligands provide targeting. This multi-functional approach achieves specific targeting without proportionally increasing system complexity, as single components serve multiple purposes
Solution Approach 2:
The patent uses intermediary molecules such as PEGylated lipids and flexible linkers that mediate between the nucleic acid payload and the targeting ligands. These intermediaries simplify the overall system architecture by providing standardized connection points and reducing direct complexity between functional elements while maintaining targeting specificity
3Productivity
If modified nucleotides are introduced to facilitate RISC processing, then gene silencing efficiency is enhanced, but the manufacturing complexity increases
Solution Approach 1:
The patent applies parameter changes by implementing specific, limited modifications at defined positions within the nucleic acid sequence (such as 2'-O-methyl at positions 2 and 14 from the 5' end of the sense strand). These targeted parameter changes enhance RISC processing efficiency while maintaining manufacturability by avoiding comprehensive modification of the entire sequence
Solution Approach 2:
The patent applies local quality by introducing modifications only at specific critical positions within the nucleic acid molecule rather than uniformly throughout. This localized approach enhances gene silencing efficiency at key functional regions while significantly reducing synthesis complexity compared to global modification strategies
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 modified nucleic acid effectively inhibits gene expression by facilitating RISC processing and achieving targeted delivery to cells, enhancing the therapeutic potential of nucleic acid-based treatments.
Implementation Method 1
Double-stranded RNA (dsRNA) has been shown to block gene expression (Fire et al, 1998 and Elbashir et al, 2001) and this has been termed RNA interference (RNAi). Short dsRNAs direct gene-specific, post-transcriptional silencing in many organisms, including vertebrates, and has provided a new tool for studying gene function. RNAi is mediated by RNA-induced silencing complex (RISC), a sequence-specific, multi-component nuclease that destroys messenger RNAs homologous to the silencing trigger.
Implementation Method 2
One method of achieving specific targeting is to conjugate a targeting moiety to the iRNA duplex agent. The targeting moiety helps in targeting the iRNA duplex agent to the required target site and there is a need to design appropriate targeting moieties for the desired receptor sites for the conjugated molecules to be taken up by the cells such as by endocytosis.
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 gene expression or inhibits its expression and therapeutic uses such as for the treatment of disease and disorders.