Mitochondrial Base Editing for Targeted LHON Mutation Correction

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Solution Overview

Problem

There is no effective treatment for Leber hereditary optic neuropathy (LHON), a mitochondrial genetic disorder caused by specific mutations in mitochondrial DNA, leading to rapid vision loss without distinct prodromal symptoms.

Innovation Solution

A base editing composition comprising fusion proteins with DNA binding proteins and deaminases, specifically targeting and correcting adenine or cytosine mutations at positions 3460, 11778, and 14484 in mitochondrial DNA to guanine or thymine, using adenine and cytosine deaminases such as APOBEC, AID, TadA, or DddAtox variants, combined with zinc finger or TALE proteins.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If base editing composition with fusion proteins is used to correct mitochondrial DNA mutations, then treatment effectiveness for LHON is improved, but device complexity and manufacturing difficulty increase

Engineering Contradiction:

Improvetreatment effectivenessVSAvoidcomposition complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The fusion protein is divided into distinct functional modules: a DNA binding protein domain (such as zinc finger or TALE protein) that targets specific mitochondrial DNA sequences, and a deaminase domain (adenine or cytosine deaminase) that performs the base conversion. This segmentation allows each module to be optimized independently while maintaining overall functionality, resolving the contradiction between treatment effectiveness and complexity by making the complex composition more manageable and designable.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The DNA binding protein component can be designed to recognize various mitochondrial DNA sequences through standardized zinc finger or TALE repeat modules, making the system universally applicable to different mutation sites. The deaminase component provides universal base conversion capability. This multi-functionality allows the same basic composition structure to treat multiple different LHON mutations, improving reliability while managing complexity through modular design.

Inventive Principle:

Principle #6Universality (Multi-functionality)

2Manufacturing precision

If specific deaminases are used to achieve precise base conversion, then manufacturing precision of the edit is improved, but ease of manufacture decreases

Engineering Contradiction:

Improvebase conversion precisionVSAvoidproduction difficulty

Core Design Contradiction:

Manufacturing precisionVSEase of manufacture

Solution Approach 1:

The patent replaces complex chemical synthesis or cellular reprogramming approaches with a targeted enzymatic mechanism. The deaminase enzyme provides precise base conversion through its catalytic activity, which is more controllable and predictable than alternative methods. This enzymatic approach achieves high manufacturing precision in terms of base conversion accuracy while simplifying the overall manufacturing process compared to traditional gene therapy vectors or complex chemical editing methods.

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

Solution Approach 2:

The patent optimizes specific parameters of the deaminase enzyme, such as its catalytic efficiency, substrate specificity, and stability, to achieve precise base conversion. By carefully selecting and engineering deaminases with optimal parameters for mitochondrial DNA editing, the system achieves high precision while maintaining ease of manufacture through well-characterized enzymatic reactions that can be produced using standard molecular biology techniques.

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

The composition effectively edits mitochondrial DNA mutations to prevent or treat LHON, potentially reversing vision loss by correcting specific genetic defects in mitochondrial genes.

Implementation Method 1

at least one of adenine deaminase and cytosine deaminase

Methodology Applied

Scientific EffectDeamination:

Implementation Method 2

at least one of adenine deaminase and cytosine deaminase

Methodology Applied

Scientific EffectDeamination:

Implementation Method 3

DNA binding protein that specifically binds to mitochondrial DNA of a patient with LHON

Methodology Applied

Scientific EffectMolecular recognition and binding:

Data Source

PatentUS20260007775A1Mitochondrial base mutation editing system for leber hereditary optic neuropathy

Publication Date: 2026.01.08 EDGENE INC

AI summary

Described herein is a base editing system for correcting mutations G3460A, G11778A, or T14484C in mitochondrial DNA of a patient with Leber hereditary optic neuropathy (LHON) to a normal genotype. Also, described herein is a method for correcting a mutation in the mitochondrial genes of a patient with LHON to a normal genotype using a base editor that recognizes specific sites in the mitochondrial genes of the patient with LHON and has an activity of specifically correcting the adenine base at position 3460 or 11778, or the cytosine base at position 14484, by using a fusion protein or a polynucleotide encoding such a fusion protein. The base editor or nucleotide described herein may correct DNA mutations specific to LHON in a cellular or extracellular in vitro environment. Thus, described herein is also the use of the substance in the prevention or treatment of LHON.