mRNA Double 3′ UTR With miR-122 Site to Reduce Liver Expression
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Solution Overview
Problem
Current mRNA delivery methods exhibit high liver expression during systemic administration, which is problematic for drugs with hepatotoxicity or systemic toxicity, necessitating methods to reduce liver expression and enhance non-liver targeted delivery.
Innovation Solution
Incorporating a miR-122 binding site between two 3′UTR sequences in the mRNA structure to exploit liver-specific miR-122 expression, thereby reducing mRNA expression in hepatocytes while maintaining stability and translation efficiency in other cell types.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional mRNA delivery methods are used for systemic administration, then mRNA can be delivered to target cells, but high liver expression occurs which causes hepatotoxicity or systemic toxicity
Solution Approach 1:
The patent applies local quality by introducing a miR-122 binding site specifically into the 3′ UTR region of the mRNA molecule. This creates a localized modification that differentially affects mRNA stability in liver cells versus other cells. The miR-122 binding site is strategically placed in the 3′ UTR to enable selective degradation only in hepatocytes where miR-122 is highly expressed, while maintaining translation efficiency in non-hepatic tissues.
Solution Approach 2:
The patent converts the harmful high liver expression into a beneficial feature by exploiting the liver-specific expression pattern of miR-122. By designing the mRNA with a miR-122 binding site, the patent turns the abundant miR-122 in liver cells (which was causing toxicity) into a tool for selective mRNA degradation in the liver, thereby protecting other tissues from toxicity while maintaining therapeutic effectiveness.
2Productivity
If mRNA is designed for high stability and translation efficiency, then protein production is enhanced, but liver-specific degradation is reduced
Solution Approach 1:
The patent segments the 3′ UTR into functional domains by introducing the miR-122 binding site as a distinct element within the 3′ UTR region. This segmentation allows the 3′ UTR to simultaneously perform multiple functions: maintaining overall mRNA stability through its structural integrity while enabling selective liver degradation through the miR-122 binding site. The segmentation creates functional independence between stability elements and liver-targeting elements.
Solution Approach 2:
The patent applies multi-functionality by designing the 3′ UTR to simultaneously provide mRNA stability, translation efficiency, and liver-specific degradation control. The 3′ UTR structure is engineered to contain multiple functional elements including the miR-122 binding site that enables it to perform both protective (stability) and selective (liver degradation) functions, making the mRNA molecule universally effective across different cell types while being specifically targeted in the liver.
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 method effectively decreases mRNA expression in the liver, enhancing non-hepatic expression and stability, as demonstrated by reduced luminescence signals in liver tissues and maintained expression in target tissues.
Implementation Method 1
Incorporating a miR-122 binding site between two 3′UTR sequences in the mRNA structure to exploit liver-specific miR-122 expression, thereby reducing mRNA expression in hepatocytes
Data Source
AI summary
An mRNA drug, which reduces expression in the liver after in vivo delivery, and a preparation method thereof. The preparation method comprises: establishing double 3′ UTR in a target mRNA, and introducing a miR-122 binding site between the double 3′ UTR, so as to effectively reduce the expression of the mRNA drug, which is delivered by means of LNP, in the liver, thereby realizing a specific inhibitory effect of miR-122 while retaining an enhancement effect of miR-122 on mRNA stability and translation efficiency. The mRNA drug can effectively reduce the expression of mRNA in the liver, realizing the efficient expression of the mRNA drug in non-hepatocellular targeted cells or tissues and increasing the effective non-hepatocyte tropism of the mRNA drug.