Uridine-Reduced mRNA Composition for Lower Immunogenicity
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Solution Overview
Problem
Existing methods for generating therapeutically applicable mRNA do not adequately address immunogenicity issues, particularly when formulated without modified nucleosides, leading to unclear immune activation and potential therapeutic interference.
Innovation Solution
Modify the nucleotide sequence of mRNA by reducing uridine content through elimination or substitution with other nucleosides, such as adenosine, guanosine, and cytidine, to decrease immunogenicity without the need for chemical modifications.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Object-affected harmful factors
If uridine residues are replaced with modified nucleosides such as pseudouridine or 2-thiouridine, then immunogenicity of mRNA is reduced, but the complexity of the manufacturing process increases due to chemical modifications
Solution Approach 1:
The patent changes the nucleotide composition parameters of mRNA by reducing uridine content and increasing adenosine content, achieving reduced immunogenicity without chemical modifications. This parameter change approach avoids the manufacturing complexity associated with chemical nucleoside modifications while still achieving the desired reduction in immune activation.
Solution Approach 2:
The patent uses standard, unmodified nucleosides (A, C, G, U) that are readily available and do not require complex chemical modification processes. This approach replaces expensive and complex modified nucleosides with simple, naturally occurring nucleosides, simplifying the manufacturing process while achieving the therapeutic goal.
2Productivity
If GC content of mRNA is maximized to reduce immune activation, then translational efficiency may be improved, but the sequence optimization becomes more complex and may affect protein expression accuracy
Solution Approach 1:
The patent changes the nucleotide composition parameters by reducing uridine content and increasing adenosine content, achieving reduced immunogenicity without the need for complex GC maximization. This approach simplifies sequence optimization while maintaining translational efficiency and avoiding the complexity of extensive codon optimization.
3Ease of manufacture
If standard nucleosides are used in mRNA formulation, then manufacturing is simplified, but immune activation remains unclear and may interfere with therapeutic effectiveness
Solution Approach 1:
The patent changes the nucleotide composition parameters by reducing uridine content (to below 20%, preferably below 15%) and increasing adenosine content (to above 35%), achieving reduced immunogenicity while using simple, unmodified nucleosides. This parameter optimization maintains both manufacturing simplicity and therapeutic reliability.
Solution Approach 2:
The patent uses feedback from observed immune activation patterns to optimize the nucleotide composition. By analyzing the relationship between nucleoside composition and immune response, the patent identifies optimal ranges for uridine and adenosine content that minimize immune activation while maintaining therapeutic effectiveness.
Data Source
AI summary
The present invention relates to RNA therapy and, in particular, decreasing immunogenicity of RNA. Specifically, the present invention provides methods for decreasing immunogenicity of RNA, said methods comprising modifying the nucleotide sequence of the RNA by reducing the uridine (U) content, wherein said reduction of the U content comprises an elimination of U nucleosides from the nucleotide sequence of the RNA and/or a substitution of U nucleosides by nucleosides other than U in the nucleotide sequence of the RNA. Using RNA having decreased immunogenicity allows administration of RNA as a drug to a subject, e.g. in order to obtain expression of a pharmaceutically active peptide or protein, without eliciting an immune response which would interfere with therapeutic effectiveness of the RNA or induce adverse effects in the subject.