Double Stranded mRNA Metabolic Stability Liver Delivery
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Solution Overview
Problem
Current non-viral gene delivery systems, particularly for mRNA, face challenges in achieving efficient and persistent protein expression in the liver due to rapid mRNA metabolism and low transfection efficiency, despite advancements in cationic lipid and nanoparticle formulations.
Innovation Solution
The use of double-stranded (ds) mRNA, which is more metabolically stable than single-stranded mRNA, is introduced for targeted gene delivery, incorporating codon-optimized sequences and untranslated regions (UTRs) to enhance stability and translation efficiency, and is delivered via hydrodynamic injection to achieve persistent protein expression in liver hepatocytes.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If single-stranded mRNA is delivered systemically to the liver, then translation efficiency is achieved, but metabolic stability is poor due to rapid RNase degradation
Solution Approach 1:
The patent changes the structural parameter of mRNA from single-stranded to double-stranded configuration. This fundamental parameter change transforms the molecular architecture to resist RNase degradation while maintaining translation capability through selective strand unwinding in target cells
Solution Approach 2:
The patent creates a composite mRNA structure consisting of two complementary strands that form a double-stranded molecule. This composite structure combines the stability of double-stranded nucleic acids with the translation efficiency of single-stranded mRNA, achieving both properties simultaneously
2Stability of the object's composition
If cationic lipid formulations are used to protect mRNA, then some stability improvement is achieved, but transfection efficiency in the liver remains very low
Solution Approach 1:
The patent extracts the protective function from external cationic lipid formulations and integrates it into the mRNA molecule itself through double-stranded structure formation. The dsRNA structure inherently protects against nucleases without requiring external stabilizing agents
Solution Approach 2:
The patent eliminates the need for cationic lipid intermediaries by using the dsRNA structure itself as the protective mechanism. The double-stranded configuration serves as an intrinsic mediator that protects mRNA from degradation while facilitating cellular uptake and translation
3Productivity
If hydrodynamic delivery is used to achieve high transfection efficiency, then expression efficiency equivalent to viral delivery is achieved, but the method is invasive and requires high volume and pressure
Solution Approach 1:
The patent enables mRNA to deliver itself to target cells efficiently through its dsRNA structure, which facilitates cellular uptake and nuclear entry without requiring hydrodynamic injection. The molecular structure itself provides the mechanisms needed for efficient delivery and expression
Solution Approach 2:
The patent replaces the mechanical hydrodynamic injection system with a molecular-level solution. The dsRNA structure enables cellular uptake and gene expression through biochemical mechanisms rather than requiring high-pressure mechanical delivery
Data Source
AI summary
Double stranded mRNA, e.g., produced in vitro, as well as method of making and using the ds mRNA, are provided.