AAV VP1 Capsid Mutations for Higher Ocular Transduction

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Solution Overview

Problem

Current recombinant AAV vectors face challenges with low transduction efficiency and restricted tissue tropisms, limiting their application as effective therapeutic agents, and there are concerns about faithful clinical translation from non-human tissues.

Innovation Solution

Development of AAV capsid proteins with specific amino acid mutations in the VP1 unique region, such as E36G, D80N, and V125A, to enhance transduction efficiency and intracellular trafficking, particularly for ocular cell types.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Productivity

If wild-type AAV capsid proteins are used, then the vector is easy to manufacture and has stable properties, but transduction efficiency is low and tissue tropism is restricted

Engineering Contradiction:

Improvetransduction efficiencyVSAvoidcapsid protein structure

Core Design Contradiction:

ProductivityVSDevice complexity

Solution Approach 1:

The patent applies parameter changes by introducing specific amino acid mutations at positions 36, 80, and 125 in the VP1 unique region of the AAV capsid protein. These mutations alter the capsid's interaction properties with cell surfaces and intracellular trafficking pathways, thereby improving transduction efficiency and expanding tissue tropism while maintaining manufacturing stability

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention applies local quality by making targeted modifications only in the VP1 unique region (positions 36, 80, 125) rather than altering the entire capsid structure. This localized approach preserves the overall capsid stability and manufacturing ease while improving specific functional properties related to cellular entry and intracellular delivery

Inventive Principle:

Principle #3Local quality

2Adaptability or versatility

If AAV vectors are designed for specific tissue targeting, then tissue tropism is improved, but transduction efficiency in other tissues decreases

Engineering Contradiction:

Improvetissue tropismVSAvoidtransduction efficiency

Core Design Contradiction:

Adaptability or versatilityVSProductivity

Solution Approach 1:

The patent applies universality by creating a capsid variant with enhanced broad-spectrum transduction capability. The mutations in the VP1 unique region enable the AAV vector to efficiently transduce multiple tissue types including ocular cells, while maintaining the ability to target other tissues effectively, thus achieving multi-functionality across different tissue tropisms

Inventive Principle:

Principle #6Universality (Multi-functionality)

3Adaptability or versatility

If non-human AAV serotypes are used, then new tissue targets are accessed, but clinical translation reliability is compromised

Engineering Contradiction:

Improvetissue target expansionVSAvoidclinical translation fidelity

Core Design Contradiction:

Adaptability or versatilityVSReliability

Solution Approach 1:

The invention applies segmentation by separating the tissue targeting function from the capsid backbone. The patent uses human AAV2 capsid proteins (ensuring clinical translation reliability) and introduces targeted mutations only in the VP1 unique region to achieve new tissue tropisms. This modular approach maintains the well-characterized human capsid structure while adding enhanced targeting capabilities through localized changes

Inventive Principle:

Principle #1Segmentation

Data Source

PatentUS20260048147A1AAV capsid proteins having mutations in the VP1 region

Publication Date: 2026.02.19 UNIV OF MASSACHUSETTS

AI summary

Aspects of the disclosure relate to compositions and methods for delivering a transgene (e.g., a transgene encoding one or more gene products) to a target cell. The disclosure is based, in part, on adeno-associated virus (AAV) capsid proteins comprising one or more amino acid substitutions in the VP1 region, and methods of using same for delivery of a transgene.