Non-self-complementary AAV Virions for Gene Transfer

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Solution Overview

Problem

Current methods for gene transfer to nervous system cells, such as those in the brain, face challenges including the blood-brain barrier and limited capacity of self-complementary AAV vectors, which restrict the length of therapeutic genes that can be incorporated, limiting therapeutic applications.

Innovation Solution

A recombinant adeno-associated virus (rAAV) virion is developed with modified capsid proteins and nervous system cell-specific promoters, allowing for efficient gene transfer through peripheral administration and enabling the packaging of non-self-complementary viral genomes of varying lengths.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Productivity

If self-complementary AAV vectors are used for gene transfer to nervous system cells, then transduction efficiency is improved, but the length of therapeutic genes that can be incorporated is limited to approximately 2 kb

Engineering Contradiction:

Improvetransduction efficiencyVSAvoidlength of therapeutic gene

Core Design Contradiction:

ProductivityVSLength of moving object

Solution Approach 1:

The patent inverts the conventional approach by using non-self-complementary (non-sc) AAV vectors instead of self-complementary (sc) vectors. This inversion allows incorporation of therapeutic genes longer than 2 kb while maintaining efficient gene transfer to nervous system cells through the blood-brain barrier, thus resolving the contradiction between transduction efficiency and gene length capacity

Inventive Principle:

Principle #13The other way round (Inversion)

Solution Approach 2:

The patent changes the key parameter of vector type from self-complementary to non-self-complementary AAV vectors. This parameter change enables the viral genome to accommodate longer therapeutic genes (exceeding 2 kb) while still achieving efficient transduction of nervous system cells, thereby resolving the limitation on gene length

Inventive Principle:

Principle #35Parameter changes

2Adaptability or versatility

If therapeutic drugs are administered systemically, then treatment coverage is improved, but the drugs are incapable of passing through the blood-brain barrier

Engineering Contradiction:

Improvetreatment coverageVSAvoidblood-brain barrier obstruction

Core Design Contradiction:

Adaptability or versatilityVSObject-affected harmful factors

Solution Approach 1:

The patent uses AAV vectors as intermediary carriers to deliver therapeutic genes across the blood-brain barrier. These viral vectors serve as mediators that can traverse the barrier and transfer genetic material to nervous system cells, enabling systemic treatment coverage while overcoming the barrier obstruction that prevents conventional drugs from reaching their target

Inventive Principle:

Principle #24Intermediary (Mediator)

3Adaptability or versatility

If the length of gene of interest is increased beyond 2 kb, then therapeutic application range is improved, but the gene cannot be incorporated into self-complementary AAV vectors

Engineering Contradiction:

Improvetherapeutic application rangeVSAvoidvector compatibility

Core Design Contradiction:

Adaptability or versatilityVSDevice complexity

Solution Approach 1:

The patent inverts the vector type from self-complementary to non-self-complementary AAV vectors, which can accommodate therapeutic genes longer than 2 kb. This inversion resolves the incompatibility issue while expanding the range of therapeutic applications to include genes that were previously too long for AAV vector incorporation

Inventive Principle:

Principle #13The other way round (Inversion)

Data Source

PatentUS11674156B2Adeno-associated virus virion for gene transfer to nervous system cells

Publication Date: 2023.06.13 JICHI MEDICAL UNIVERSITY

AI summary

The present invention provides a means for transferring a therapeutic gene of interest into a nervous system cell by a highly-efficient and simpler means. More specifically, the present invention provides a recombinant vector that uses an adeno-associated virus (AAV), a method for manufacturing the recombinant vector, and a method for using the recombinant vector. More specifically, recombinant adeno-associated virus virions, which are capable of passing through the brain-brain barrier, for transferring a therapeutic genes of interest into a nervous system cell in a highly-efficient manner, a drug composition containing the recombinant adeno-associated virus virions, a method for manufacturing the recombinant adeno-associated virus virions, and a kit or the like are provided.