Position-Specific Modified Synthetic tRNA for Lower Immunogenicity
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Solution Overview
Problem
Naturally occurring tRNAs are immunogenic and trigger a strong immune response in humans, making them unsuitable for therapeutic applications, while modifications that reduce immunogenicity in mRNA are not applicable due to potential disruption of tRNA secondary structure and function.
Innovation Solution
Development of synthetic tRNAs with specific modified nucleotides at defined positions, such as m5C, m6A, Ψ, and 2′-OMe, to reduce immunogenicity while maintaining functional integrity and decoding activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If unmodified nucleotides are used in tRNA, then the tRNA can be synthesized and introduced into target tissue, but the tRNA triggers a strong immune response in humans
Solution Approach 1:
The patent applies local quality by introducing modifications at specific positions within the tRNA molecule rather than uniformly across all nucleotides. The modified nucleotides are placed at defined positions (e.g., positions 1, 10, 19, 28, 37, 46, 55, 64, 73) to reduce immunogenicity while preserving the essential secondary structure and function of the tRNA. This localized modification strategy allows the tRNA to evade immune detection at critical sites while maintaining its functional integrity.
Solution Approach 2:
The patent employs parameter changes by chemically modifying specific nucleotide bases at defined positions within the tRNA sequence. Modifications include but are not limited to 2'-O-methylation, ribothymidine, pseudouridine, and other chemically altered nucleotides. These parameter changes in nucleotide composition and structure directly reduce the immunogenicity of the tRNA while preserving its ability to function in protein synthesis and serve as therapeutic agents for nonsense mutation suppression.
2Object-affected harmful factors
If modified nucleotides are introduced to reduce immunogenicity, then immune response is reduced, but the tRNA secondary structure and function may be disrupted
Solution Approach 1:
The patent carefully selects specific positions for nucleotide modifications (e.g., positions 1, 10, 19, 28, 37, 46, 55, 64, 73) that are less critical for maintaining the overall secondary structure and function of the tRNA. By modifying nucleotides at these specific locations rather than at critical functional sites such as the anticodon loop or acceptor stem, the patent preserves the tRNA's ability to bind amino acids, recognize codons, and participate in protein synthesis while still achieving reduced immunogenicity.
Solution Approach 2:
The patent applies partial modification rather than complete modification of all nucleotides. Only specific nucleotides at defined positions are modified, leaving the majority of the tRNA sequence unmodified to maintain its natural structure and function. This partial action approach ensures that the essential functional elements of the tRNA remain intact while still providing sufficient modification to reduce immune recognition and response.
3Object-affected harmful factors
If multiple modified nucleotides are used, then immunogenicity is reduced more effectively, but the complexity of synthesis increases
Solution Approach 1:
The patent divides the tRNA synthesis process into manageable segments by specifying modifications at discrete, predefined positions rather than requiring uniform modification throughout the entire molecule. This segmentation allows for modular synthesis approaches where modified nucleotides can be incorporated at specific sites using standard oligonucleotide synthesis techniques, thereby reducing the overall complexity compared to attempting comprehensive modification of all nucleotides.
Solution Approach 2:
The patent establishes a defined set of modification parameters including specific nucleotide types (2'-O-methyl, ribothymidine, pseudouridine, etc.) at specific positions. By standardizing these parameters and limiting modifications to a defined subset of nucleotides rather than all nucleotides, the patent makes the synthesis process more tractable and scalable while still achieving effective reduction of immunogenicity.
Data Source
AI summary
A synthetic transfer RNA with at least one modified nucleotide or combination of modified nucleotides at a unique position or a unique pattern of modified nucleotides.