Modified mRNA Codon Composition for Low-Immunogenic Protein Therapy
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Solution Overview
Problem
mRNA-based therapeutics for protein replacement therapies face challenges due to their inherent immunostimulatory properties, which can cause undesired immune responses, especially in chronic treatments requiring repeated administration.
Innovation Solution
Modifying the mRNA by increasing the cytosine-content of the coding region and optionally replacing relatively rare codons with more frequent codons to reduce immunogenicity and immunostimulatory capacity while maintaining efficient protein expression.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If mRNA is used for protein replacement therapy, then protein expression can be achieved, but immunostimulatory properties cause undesired immune responses
Solution Approach 1:
The patent modifies the mRNA sequence by changing nucleotide composition (increasing cytosine content to 35-45%), adjusting codon usage frequency, and modifying GC content to 40-50%. These parameter changes reduce the mRNA's affinity for immune receptors like TLR7 and TLR8, thereby decreasing immunostimulatory properties while preserving protein expression capability
Solution Approach 2:
The patent creates modified copies of the original mRNA sequence that maintain the same coding information (amino acid sequence) but with altered nucleotide composition. These copied sequences use synonymous codons with different nucleotide makeup to reduce immune recognition while preserving the encoded protein function
2Duration of action of stationary object
If mRNA is administered repeatedly for chronic disease treatment, then therapeutic effect can be maintained, but cumulative immune responses increase
Solution Approach 1:
The modified mRNA sequences with optimized nucleotide composition (35-45% cytosine, 40-50% GC content) and adjusted codon usage frequencies create a formulation that elicits reduced immune responses. This allows repeated administrations over extended periods without cumulative immune activation, enabling chronic disease treatment protocols
3Object-generated harmful factors
If mRNA sequence is modified to reduce immunogenicity, then immune responses decrease, but protein expression efficiency may be affected
Solution Approach 1:
The patent optimizes multiple parameters simultaneously: cytosine content (35-45%), GC content (40-50%), and codon usage frequency. These changes are designed to reduce immune recognition while maintaining or enhancing translation efficiency. The modified sequences incorporate frequent codons that match host cell tRNA pools, ensuring efficient protein synthesis
Solution Approach 2:
The patent applies different modification strategies to specific regions of the mRNA molecule. The coding region undergoes cytosine enrichment and codon optimization, while maintaining appropriate structural elements. This localized optimization reduces immunogenicity in critical regions without compromising overall protein expression efficiency
Data Source
AI summary
The present invention provides a method for providing modified mRNAs of reduced immunogenicity and/or immunostimulatory capacity for use in protein replacement therapy. The invention further provides modified mRNAs and pharmaceutical compositions comprising the modified mRNAs according to the invention for use in protein replacement therapy.