Nucleotide-Modified mRNA for Permanent Gene Correction

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Solution Overview

Problem

Current gene therapeutic efforts using DNA-based or viral vectors are largely unsuccessful in treating severe genetic disorders like surfactant protein B deficiency and cystic fibrosis due to barriers in delivering foreign vectors to the lungs and health risks associated with viral vectors.

Innovation Solution

The use of nucleotide-modified messenger RNA (nec-mRNA) encoding nucleases, which is transfected into target cells to initiate a double-strand break in the DNA, stimulating homologous recombination for permanent correction of genetic alterations, avoiding integration into the host genome and reducing immunogenicity and toxicity.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If DNA-based or viral vectors are used for gene therapy, then genetic correction can be achieved, but delivery barriers in the lungs and health risks (oncogene activation, immunogenicity) occur

Engineering Contradiction:

Improvegene correction effectivenessVSAvoidimmunogenicity and toxicity

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies parameter changes by modifying the chemical structure of nucleotides in mRNA (replacing uridine with pseudouridine and cytidine with 5-methylcytidine) to reduce immunogenicity while maintaining gene correction effectiveness. This chemical parameter modification resolves the contradiction between therapeutic effectiveness and harmful immunogenic responses.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent uses transient mRNA instead of permanent viral vectors or integrated DNA. The mRNA is temporary and degrades naturally after delivering its genetic payload, avoiding long-term safety risks like oncogene activation while still achieving the desired gene correction effect during the active period.

Inventive Principle:

Principle #27Cheap short-living objects (Disposable)

2Object-affected harmful factors

If nucleotide-modified mRNA is used for temporary protein expression, then immunogenicity is reduced, but permanent gene correction cannot be achieved

Engineering Contradiction:

ImproveimmunogenicityVSAvoidduration of therapeutic effect

Core Design Contradiction:

Object-affected harmful factorsVSDuration of action of stationary object

Solution Approach 1:

The patent uses the transient mRNA to deliver nuclease enzymes that create double-strand breaks in the genomic DNA, which then triggers the cell's own repair mechanisms to permanently correct the genetic defect. The preliminary action of mRNA delivery enables a permanent outcome without requiring the mRNA itself to be permanent.

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The mRNA acts as an intermediary that temporarily delivers the therapeutic nuclease to the cell, where it catalyzes the permanent genetic correction. The intermediary (mRNA) is temporary and degrades, but the result it produces (corrected DNA) is permanent, resolving the contradiction between transient delivery and permanent effect.

Inventive Principle:

Principle #24Intermediary (Mediator)

3Ease of operation

If viral vectors are used for gene delivery, then genetic material can be delivered to target cells, but health risks such as oncogene activation and immune responses occur

Engineering Contradiction:

Improvegene delivery capabilityVSAvoidhealth risks

Core Design Contradiction:

Ease of operationVSObject-generated harmful factors

Solution Approach 1:

The patent replaces the viral delivery system (biological/mechanical complex system) with a simpler chemical system (synthetic modified mRNA). This substitution maintains the ability to deliver genetic material while eliminating the health risks associated with viral vectors, such as oncogene activation and strong immune responses.

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

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 enables a stable and targeted correction of genetic alterations, potentially leading to lifelong expression of the corrected protein, improving treatment outcomes for severe lung diseases such as surfactant protein B deficiency and cystic fibrosis.

Implementation Method 1

which is transfected into target cells to initiate a double-strand break in the DNA

Methodology Applied

Scientific EffectDouble-strand break:

Implementation Method 2

stimulating homologous recombination for permanent correction of genetic alterations

Methodology Applied

Scientific EffectHomologous recombination:

Implementation Method 3

nucleotide-modified messenger RNA (nec-mRNA) encoding nucleases, which is transfected into target cells

Methodology Applied

Scientific EffectNucleotide modification:

Data Source

PatentUS11332726B2Permanent gene correction by means of nucleotide-modified messenger RNA

Publication Date: 2022.05.17 HELMHOLTZ ZENT FUER INFEKTIONSFORSCHUNG GMBH FU

AI summary

The present invention relates to a nucleotide-modified messenger RNA for the permanent correction of a genetic alteration on a DNA. The invention further relates to a nucleotide-modified messenger RNA in combination with a repair template. It also relates to a pharmaceutical composition. It finally relates to methods for the correction of a genetic alteration on a DNA.