Engineered AAV9 Capsids for Precise CNS Gene Delivery

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Solution Overview

Problem

Existing AAV serotypes have limited tissue tropism, particularly for the central nervous system, restricting the development of effective gene therapies for neurological disorders.

Innovation Solution

Development of a library of AAV capsids with engineered polypeptides containing a 7-amino acid insertion between positions Q588 and A589 of the AAV9 capsid, enhancing CNS tropism and transduction efficiency.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Adaptability or versatility

If naturally occurring AAV serotypes are used for gene delivery, then the virus particle is physico-chemically stable and non-pathogenic, but the tissue tropism is limited and mostly broad, restricting effective targeting of the nervous system

Engineering Contradiction:

Improvetissue tropismVSAvoidtargeting precision

Core Design Contradiction:

Adaptability or versatilityVSReliability

Solution Approach 1:

The patent applies capsid engineering by introducing specific amino acid mutations at defined positions in the AAV9 capsid protein (e.g., positions 588-589, 600-601, 612-613) to alter the virus's tissue tropism. These parameter changes in the capsid sequence enable enhanced CNS targeting while maintaining the stable and safe characteristics of AAV9

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention modifies specific local regions of the capsid protein at precise amino acid positions to achieve enhanced CNS tropism. By making localized changes at specific sites (such as the 7-mer insertion at positions 588-589), the patent improves targeting precision in the nervous system without requiring complete redesign of the entire capsid structure

Inventive Principle:

Principle #3Local quality

2Productivity

If AAV capsid engineering is performed to improve CNS tropism, then transduction efficiency in brain regions is enhanced, but the capsid structure becomes more complex

Engineering Contradiction:

Improvetransduction efficiencyVSAvoidcapsid structure

Core Design Contradiction:

ProductivityVSDevice complexity

Solution Approach 1:

The patent achieves improved transduction efficiency by introducing specific amino acid mutations at defined positions in the capsid protein sequence. These parameter changes (e.g., 7-mer insertion at positions 588-589, mutations at 600-601 and 612-613) enhance CNS tropism and transduction efficiency while maintaining reasonable structural complexity

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The capsid engineering approach segments the capsid protein into specific functional regions, with mutations introduced at particular amino acid positions (such as the 7-mer insertion site between positions 588-589). This segmentation allows targeted modification of specific capsid regions responsible for CNS tropism without redesigning the entire capsid structure

Inventive Principle:

Principle #1Segmentation

Data Source

PatentUS12509490B2AAV capsids for targeting nervous system and uses thereof

Publication Date: 2025.12.30 SHANGHAI VITALGEN BIOPHARMA CO LTD

AI summary

The present invention provides new adeno-associated viral (AAV) capsids, and recombinant AAV (rAAV) virion comprising the said capsid and a vector genome comprising a transgene. The rAAV virion comprising the novel capsid shows improved CNS-targeting infection efficiencies and/or increased expression levels of the transgene. Also provided are a method for treating a disease, including administration of the rAAV virion comprising the said AAV capsid to a subject in need thereof.