Therapeutic RNA with Nucleotide Modifications to Reduce Immunostimulation

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Solution Overview

Problem

Therapeutic RNA-based replacement therapies face challenges in minimizing immunostimulatory properties while maintaining protein expression levels and avoiding immune responses, particularly in chronic disease treatments where repeated administration is necessary, due to the inherent immunogenicity of RNA molecules that can trigger innate immune responses.

Innovation Solution

Co-administration of a therapeutic RNA with an antagonist of RNA sensing pattern recognition receptors, such as Toll-like receptors 7 and 8, to reduce innate immune stimulation and enhance protein expression by modulating the immune response.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If therapeutic RNA is administered for protein replacement therapy, then protein expression is achieved, but innate immune responses are triggered causing inflammation and reduced therapeutic efficacy

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidinnate immune response

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent introduces modified nucleotides as intermediaries that mediate between the therapeutic RNA and the cellular machinery. These modified nucleotides (such as pseudouridine, N1-methylpseudouridine, 5-methylcytidine) serve as a bridge that allows the RNA to be translated by ribosomes while evading detection by pattern recognition receptors, thus resolving the contradiction between achieving protein expression and avoiding immune activation

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The patent applies parameter changes by chemically modifying the nucleotide composition of the RNA therapeutic. By changing the chemical parameters of the nucleotides (adding methyl groups, creating pseudouridine structures), the RNA's properties are altered to reduce immunogenicity while maintaining or enhancing translation efficiency, thereby resolving the contradiction between protein expression and immune response avoidance

Inventive Principle:

Principle #35Parameter changes

2Object-affected harmful factors

If modified nucleotides are introduced to reduce immune stimulation, then innate immune response is decreased, but protein expression or translation activity may be reduced

Engineering Contradiction:

Improveimmune stimulationVSAvoidprotein expression

Core Design Contradiction:

Object-affected harmful factorsVSProductivity

Solution Approach 1:

The patent systematically explores different nucleotide modification parameters (type of modification, position in the sequence, frequency of modification) to find the optimal balance. By adjusting these parameters, the RNA achieves both reduced immune stimulation and maintained or enhanced protein expression, resolving the contradiction between lowering immunogenicity and preserving therapeutic efficacy

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent creates composite RNA structures by combining different types of modified nucleotides in specific patterns and ratios. This composite approach allows the RNA to simultaneously exhibit reduced immunogenicity from certain modifications while maintaining translation efficiency through other modifications, thereby resolving the contradiction between immune avoidance and protein expression

Inventive Principle:

Principle #40Composite materials

3Duration of action of stationary object

If therapeutic RNA is administered repeatedly for chronic disease treatment, then sustained therapeutic effect is achieved, but cumulative immune responses and reactogenicity increase

Engineering Contradiction:

Improvetreatment durationVSAvoidreactogenicity

Core Design Contradiction:

Duration of action of stationary objectVSObject-affected harmful factors

Solution Approach 1:

The patent employs specific nucleotide modification parameters that provide long-lasting immune evasion properties, allowing repeated administrations without cumulative immune activation. The modified nucleotides create a stable molecular signature that consistently avoids detection across multiple dosing events, enabling chronic treatment regimens while minimizing reactogenicity

Inventive Principle:

Principle #35Parameter changes

Applied Scientific Principles

This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.

Function Achieved in This Case

This approach reduces immunostimulatory effects and increases or prolongs protein expression, making it suitable for chronic medical treatments by minimizing adverse reactions and maintaining therapeutic efficacy.

Implementation Method 1

an antagonist of at least one RNA sensing pattern recognition receptor, such as toll-like receptors 7 and 8

Methodology Applied

Scientific EffectPattern recognition receptor binding:

Data Source

PatentUS20220296628A1RNA combinations and compositions with decreased immunostimulatory properties

Publication Date: 2022.09.22 CUREVAC SE

AI summary

The invention relates inter alia to a combination comprising (i) a first component comprising at least one therapeutic RNA and (ii) a second component comprising at least one antagonist of at least one RNA sensing pattern recognition receptor. Further provided are compositions comprising at least one therapeutic RNA and at least one antagonist of at least one RNA sensing pattern recognition receptor. The combination of the two components is able to reduce immunostimulatory properties of the first component as well as promote expression after administration. Additionally, first and second medical uses, and methods of treating or preventing diseases, disorders or conditions are provided.