Modified RNA Constructs for Immune Evasion
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Solution Overview
Problem
RNA therapeutics, such as mRNA and saRNA, face challenges in translation from small animal models to human clinical settings due to innate immune sensing, leading to interferon responses and reduced efficacy, as they are detected by innate immune mechanisms, inhibiting protein expression.
Innovation Solution
Development of RNA constructs that encode both therapeutic biomolecules and non-viral innate modulatory proteins to inhibit innate immune responses, allowing for higher protein expression and translation by co-localizing the RNA and immune modulating proteins within host cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If RNA therapeutics (mRNA/saRNA) are administered to achieve high protein expression, then therapeutic efficacy is improved, but innate immune sensing triggers interferon responses that inhibit translation
Solution Approach 1:
The patent introduces an intermediary molecule (modified nucleotide analog such as pseudouridine, N1-methylpseudouridine, or 5-methylcytidine) that mediates between the RNA therapeutics and the host cell's innate immune system. These modified nucleotides are incorporated into the RNA sequence to reduce recognition by pattern recognition receptors (RIG-I, MDA5, PKR), thereby suppressing interferon responses while maintaining high protein expression levels
Solution Approach 2:
The patent changes the chemical parameters of the RNA molecule by substituting standard nucleotides with modified analogs. This parameter change (chemical modification of nucleotide structure) alters the RNA's immunogenicity profile, reducing its detectability by innate immune sensors while preserving its ability to be translated into protein at high levels
2Object-affected harmful factors
If modified ribonucleotides are used to reduce innate sensing, then interferon induction is reduced, but modified mRNA is not completely undetectable and still results in some protein silencing
Solution Approach 1:
The patent employs multiple modified nucleotide analogs that can be used individually or in combination (pseudouridine, N1-methylpseudouridine, 5-methylcytidine, and others). This multi-functional approach allows selection or combination of modifications that target different aspects of immune recognition, providing more complete evasion of both interferon induction and protein silencing mechanisms
Solution Approach 2:
The patent creates composite RNA molecules incorporating multiple types of modified nucleotides within the same RNA sequence. This composite structure combines the benefits of different modifications to achieve synergistic effects in reducing immune detection while maintaining high translational efficiency and protein expression
3Duration of action of moving object
If saRNA vectors are used to achieve prolonged protein expression, then expression duration is extended, but large size and double stranded regions trigger MDA5 pathway and inhibit self-amplification
Solution Approach 1:
The patent introduces modified nucleotides as intermediary molecules within the saRNA structure that mediate between the large dsRNA configuration and the MDA5 sensing pathway. These modifications reduce the ability of MDA5 to recognize and bind to the saRNA, thereby preventing pathway activation while preserving the self-amplification capability and prolonged expression duration
Solution Approach 2:
The patent changes the chemical parameters of the saRNA by incorporating modified nucleotides that alter the physical and immunological properties of the RNA. These parameter changes reduce the immunogenicity of the large dsRNA structure without compromising its functional properties of self-amplification and sustained protein expression
Data Source
AI summary
The present invention relates to RNA constructs, and particularly, although not exclusively, to mRNA constructs and saRNA replicons and to nucleic acids and expression vectors encoding such RNA constructs. The invention extends to the use of such RNA constructs in therapy, for example in treating diseases and/or in vaccine delivery. The invention extends to pharmaceutical compositions comprising such RNA constructs, and methods and uses thereof.