Self-Amplifying RNA Constructs with Innate Inhibitor Proteins
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Solution Overview
Problem
Existing RNA therapeutics face challenges in translating from small animal efficacy to human clinical trials due to innate immune system sensing, leading to interferon responses and reduced protein expression, with current solutions like modified ribonucleotides and saRNA vectors still triggering antiviral responses.
Innovation Solution
Development of RNA constructs encoding both therapeutic biomolecules and innate inhibitor proteins (IIPs) that block innate immune system machinery, ensuring colocalization and self-amplification to enhance protein expression.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If self-amplifying RNA vectors are used to achieve high protein expression levels, then protein expression is improved, but innate immune sensing triggers antiviral responses that limit expression
Solution Approach 1:
The patent introduces an intermediary molecule (innate inhibitor protein or modified nucleotide sequence) that mediates between the self-amplifying RNA vector and the innate immune system. This intermediary blocks the harmful sensing interaction while allowing the beneficial protein expression to proceed, effectively resolving the contradiction between high productivity and immune detection
Solution Approach 2:
The patent converts the harmful innate immune response into a beneficial outcome by using the immune system's own recognition mechanisms against itself. The modified nucleotide sequences or inhibitor proteins exploit the immune sensing pathways to actually suppress antiviral responses, turning the previously harmful immune detection into a mechanism that enhances rather than limits protein expression
2Object-affected harmful factors
If modified ribonucleotides are used to reduce innate detection, then immune sensing is reduced, but interferon activation and protein silencing still occur
Solution Approach 1:
The patent applies parameter changes by systematically modifying multiple aspects of the RNA construct simultaneously - using specific modified nucleotide sequences (such as pseudouridine, 5-methylcytidine) in combination with optimized codon usage, secondary structure elements, and 5' cap modifications. This multi-parameter optimization reduces innate detection more effectively than single modifications while maintaining or enhancing protein expression reliability
Solution Approach 2:
The patent creates a composite RNA construct that combines multiple modified nucleotide types, structural elements, and sequence optimizations into a single integrated molecule. This composite approach allows the different components to work synergistically - the modified nucleotides reduce immune detection while the structural elements maintain stability and translation efficiency, achieving both reduced detection and reliable expression
3Productivity
If large size and double stranded regions are present in saRNA, then self-amplification capacity is improved, but MDA5 pathway triggers stronger innate responses
Solution Approach 1:
The patent applies local quality by creating heterogeneous structures within the RNA molecule - alternating between single-stranded regions (which avoid MDA5 detection) and localized double-stranded regions (which provide necessary structural functions and amplification capacity). This spatial variation in structure allows different parts of the molecule to fulfill different functions while minimizing overall immune detection
Solution Approach 2:
The patent introduces dynamic elements that allow the RNA structure to change over time - using sequences that can transition between single-stranded and double-stranded conformations, or that adopt different structural states during different phases of the amplification cycle. This dynamic restructuring allows the molecule to maintain amplification capacity while periodically reducing MDA5 pathway activation
Data Source
AI summary
The invention relates to RNA constructs encoding (i) at least one therapeutic biomolecule; and (ii) at least one innate inhibitor protein (IIP). The constructs are RNA replicons and saRNA molecules, and the invention includes genetic constructs or vectors encoding such RNA replicons. The invention extends to the use of such RNA constructs and replicons 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.