Modified Polyribonucleotides Reducing Immunogenicity in RNA Therapeutics
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
RNA therapeutics face challenges with immunogenicity and payload expression, including high doses and repeated dosing, due to innate immune response activation and instability of therapeutic formulations.
Innovation Solution
Polyribonucleotides modified with N4-acetylcytidine and 5-hydroxymethyluridine reduce immunogenicity by minimizing innate immune response activation and enhance payload expression, allowing for repeated dosing and higher doses without efficacy reduction.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If RNA therapeutics are administered at high doses or repeatedly dosed, then therapeutic efficacy is improved, but immunogenicity increases causing innate immune response activation
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure of ribonucleotides within the RNA therapeutic. Specifically, it incorporates modified ribonucleotides such as N4-acetylcytidine (ac4C) and 5-hydroxymethyluridine (5hmU) at controlled percentages (e.g., 5-100% substitution). This chemical parameter modification reduces the immunogenicity of the RNA while maintaining its therapeutic function, thereby enabling higher doses and repeated dosing without triggering harmful immune responses
Solution Approach 2:
The patent creates a composite RNA structure by combining modified ribonucleotides (ac4C, 5hmU) with unmodified ribonucleotides in specific ratios. This composite approach allows the RNA therapeutic to maintain its functional properties while the modified components reduce immunogenicity. The synergistic combination of different nucleotide types enables both high payload expression and reduced immune activation
2Duration of action of stationary object
If RNA therapeutics are administered repeatedly, then sustained therapeutic effect is improved, but innate immune response activation increases
Solution Approach 1:
The patent modifies the chemical parameters of the RNA by incorporating ac4C and 5hmU modified ribonucleotides, which change the physical and immunological properties of the RNA. These parameter changes reduce recognition by innate immune sensors while maintaining stability and expression, enabling repeated dosing with sustained therapeutic effect without triggering immune responses
Solution Approach 2:
The modified RNA therapeutics provide continuous useful action through sustained payload expression across multiple dosing events. The ac4C and 5hmU modifications ensure that the RNA remains stable and functional over time, maintaining therapeutic levels of expression while avoiding immune-mediated clearance that would interrupt continuous action
3Object-affected harmful factors
If modified ribonucleotides are incorporated into polyribonucleotide, then immunogenicity is reduced, but manufacturing complexity increases
Solution Approach 1:
The patent achieves reduced immunogenicity through parameter changes in the nucleotide composition, specifically incorporating ac4C and 5hmU modified ribonucleotides at optimized percentages. While this increases manufacturing complexity, the use of established modification chemistry and controlled incorporation ratios (5-100%) makes the process feasible with current synthetic RNA manufacturing capabilities
Data Source
AI summary
Disclosed herein is a modified ribonucleotide comprising a nucleoside comprising N4-acetylcytidine and/or 5-hydroxymethyluridine, and polyribonucleotides comprising the same. Also provided herein are compositions comprising a polyribonucleotide of the present disclosure and methods of making and using the same.