Modified AAV Capsid Composition for Immune-Evasive Tissue Targeting

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Solution Overview

Problem

Current AAV vectors face challenges due to preexisting immunity and restricted tissue tropism, limiting their effectiveness in gene therapy applications.

Innovation Solution

Development of a recombinant AAV (rAAV) with a modified AAVrh.91 capsid containing heterogeneous populations of vp1, vp2, and vp3 proteins with deamidated asparagines, optimized for targeted delivery to specific tissues such as the central nervous system, heart, and skeletal muscle, and formulated for intrathecal, intravenous, intranasal, or intramuscular delivery.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If current AAV vectors are used for gene delivery, then they provide long-term gene expression and lack pathogenicity, but they are hindered by preexisting immunity and restricted tissue tropism

Engineering Contradiction:

Improvegene expression efficacyVSAvoidtissue tropism

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent applies parameter changes by modifying the amino acid sequence of the AAV capsid protein (specifically AAVrh.91 variants with deamidated asparagine residues at positions 57, 383, and 512). These chemical modifications to the capsid structure alter its physical and biological properties, enabling expanded tissue tropism and reduced preexisting immunity while maintaining long-term gene expression capability

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention creates composite viral vectors by combining modified AAVrh.91 capsid proteins with heterologous nucleic acid sequences. The capsid serves as a protective composite structure that delivers therapeutic genes to diverse tissue types, integrating the benefits of AAV's long-term expression with enhanced tissue specificity through the modified capsid composition

Inventive Principle:

Principle #40Composite materials

2Ease of manufacture

If current AAV vectors are used for gene delivery, then they are relatively easily manipulated with simple genetic components, but they face preexisting immunity that limits their effectiveness

Engineering Contradiction:

Improvevector production simplicityVSAvoidpreexisting immunity

Core Design Contradiction:

Ease of manufactureVSObject-affected harmful factors

Solution Approach 1:

The patent modifies the AAV capsid's amino acid parameters (deamidation of asparagine residues) to create variants that escape preexisting immunity. These parameter changes are implemented through straightforward genetic modifications to the capsid encoding sequence, maintaining ease of manufacture while overcoming immune barriers

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention creates modified copies of the AAVrh.91 capsid with specific amino acid substitutions. These copied and slightly modified capsid structures retain the original's ease of production while gaining resistance to preexisting immunity, allowing efficient replication and manufacturing of improved vectors

Inventive Principle:

Principle #26Copying

Data Source

PatentUS12516351B2AAV capsids and compositions containing same

Publication Date: 2026.01.06 THE TRUSTEES OF THE UNIV OF PENNSYLVANIA

AI summary

Provided herein are novel AAV capsids and rAAV comprising the same. In one embodiment, vectors employing a novel AAV capsid show increased transduction of a selected target tissue as compared to a prior art AAV.