Brain-Targeting AAV Capsid Mutants for Neuronal Gene Delivery

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Solution Overview

Problem

Existing AAV vectors lack efficient tropism for brain-specific gene delivery, limiting their application in targeted gene transduction to this organ.

Innovation Solution

Development of AAV capsid protein mutants with specific amino acid sequences, such as SEQ ID NOS: 15-62, which are introduced into the AAV capsid at positions like 588-589 of AAV2 VP1, enhancing brain-targeting capabilities.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Adaptability or versatility

If wild-type AAV capsid protein is used, then general gene delivery capability is maintained, but brain-specific tropism is insufficient

Engineering Contradiction:

Improvebrain-specific tropismVSAvoidgene transduction efficiency into brain

Core Design Contradiction:

Adaptability or versatilityVSProductivity

Solution Approach 1:

The invention introduces a peptide with a specific amino acid sequence (SEQ ID NO: 15-62) at a localized position (amino acid 588-589) of the AAV2 capsid protein VP1. This local modification confers brain-specific tropism to the otherwise generalist AAV capsid, enabling targeted gene delivery to brain cells while maintaining overall capsid functionality.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The invention modifies the amino acid sequence parameter of the capsid protein by inserting a specific peptide sequence at position 588-589 of VP1. This parameter change fundamentally alters the tropism profile of the AAV capsid from general delivery to brain-specific targeting, while preserving other functional properties of the virus particle.

Inventive Principle:

Principle #35Parameter changes

2Adaptability or versatility

If AAV capsid protein is modified to achieve brain-targeting, then brain tropism is improved, but capsid structure and assembly may be affected

Engineering Contradiction:

Improvebrain-targeting capabilityVSAvoidcapsid assembly stability

Core Design Contradiction:

Adaptability or versatilityVSReliability

Solution Approach 1:

The peptide insertion is confined to a specific location (amino acid 588-589) in the VP1 protein, leaving the rest of the capsid structure unchanged. This localized modification approach minimizes disruption to overall capsid assembly and stability while achieving the desired brain-targeting function.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

Instead of extensively redesigning the entire capsid structure, the invention uses a minimal partial modification (insertion of a short peptide sequence) to achieve brain-targeting. This partial action approach maintains the reliability of capsid assembly while introducing the new function.

Inventive Principle:

Principle #16Partial or excessive action

Data Source

PatentUS12421526B2AAV mutant having brain-targeting property

Publication Date: 2025.09.23 TAKARA BIO INC

AI summary

The present invention provides a nucleic acid which encodes an adeno-associated virus (AAV) capsid protein mutant that contains a peptide comprising an amino acid sequence selected from the group consisting of SEQ ID Nos. 15 to 62 or a peptide comprising an amino acid sequence produced by substituting, deleting, inserting and/or adding one or several amino acid residues in an amino acid sequence selected from the group consisting of SEQ ID Nos. 15 to 62; DNA comprising the nucleic acid; a cell harboring the DNA; and a method for producing the cell.