Asymmetric AAV ITR Platform for Higher Expression and Lower Genotoxicity

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Solution Overview

Problem

Adeno-associated virus (AAV) faces challenges with poor DNA packaging ability, reduced gene expression rates due to strand competition, and potential genotoxicity when delivering genes, particularly in host cells.

Innovation Solution

The AAV complex is modified with asymmetrically altered inverted terminal repeats (ITRs) to enhance DNA packaging, increase transgene expression efficiency, and reduce genotoxicity by preventing integration into host genomes.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Productivity

If AAV uses standard ITR structure for viral replication, then viral replication is maintained, but DNA packaging ability is poor and gene expression rate is reduced

Engineering Contradiction:

Improvegene expression rateVSAvoidDNA packaging ability

Core Design Contradiction:

ProductivityVSReliability

Solution Approach 1:

The patent applies asymmetry by modifying one of the two inverted terminal repeats (ITRs) while leaving the other unchanged. Specifically, the 5' ITR is modified to enhance DNA packaging ability and gene expression, while the 3' ITR remains wild-type to maintain viral replication functions. This asymmetric modification resolves the contradiction by optimizing packaging and expression without sacrificing replication capacity.

Inventive Principle:

Principle #4Asymmetry

Solution Approach 2:

The patent applies local quality by making specific modifications only to the 5' ITR region while maintaining the wild-type structure of the 3' ITR. The 5' ITR modification locally enhances DNA packaging and gene expression properties, while the 3' ITR retains its original function for viral replication, thus resolving the overall system contradiction through localized optimization.

Inventive Principle:

Principle #3Local quality

2Productivity

If AAV delivers genes to host cells, then gene delivery is achieved, but genotoxicity and insertion into host genome occur

Engineering Contradiction:

Improvegene delivery efficiencyVSAvoidgenotoxicity

Core Design Contradiction:

ProductivityVSObject-affected harmful factors

Solution Approach 1:

The patent extracts and removes the harmful integration function from the AAV system by modifying the 5' ITR to prevent strand invasion into host chromosomes. This extraction eliminates genotoxicity while preserving the beneficial gene delivery function, as the modified ITR allows gene transfer without integrating into the host genome.

Inventive Principle:

Principle #2Taking out (Extraction)

3Quantity of substance

If AAV packaging capacity is increased to deliver larger genes, then gene delivery capability improves, but DNA packaging ability deteriorates due to ITR constraints

Engineering Contradiction:

Improvegene size capacityVSAvoidDNA packaging ability

Core Design Contradiction:

Quantity of substanceVSProductivity

Solution Approach 1:

The patent changes the structural parameters of the 5' ITR through modification, which alters its properties to enhance DNA packaging capacity. This parameter change allows the AAV system to accommodate larger gene sizes while maintaining efficient packaging, resolving the contradiction between gene size capacity and packaging ability.

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentUS20260028646A1Modified complex platform of adeno-associated virus with improved rate of expression of loaded genes and reduced genotoxicity

Publication Date: 2026.01.29 GENECRAFT GMBH

AI summary

Described herein is an adeno-associated virus (AAV) complex platform including an asymmetrically modified inverted terminal repeat (ITR). The AAV complex has advantages of increased productivity and expression efficiency of a transgene, and decreased genotoxicity, by having an asymmetric ITR in which any one of two ITRs is modified. Also, described herein is a composition comprising the adeno-associated virus complex and a method of gene therapy.