Deamidated AAVrh75 Capsids for Gene Therapy Tropism

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Solution Overview

Problem

Current AAV vectors used in gene therapy face limitations due to preexisting immunity and restricted tissue tropism, which hinders their effectiveness in clinical applications.

Innovation Solution

Development of recombinant adeno-associated virus (rAAV) vectors with specific capsid modifications, including deamidated AAVrh75, AAVhu71/74, AAVhu79, and other serotype-specific capsids, to enhance transduction efficiency and tissue targeting.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional AAV vectors are used for gene therapy, then long-term gene expression and low immunogenicity are achieved, but preexisting immunity and restricted tissue tropism limit effectiveness

Engineering Contradiction:

Improvegene therapy effectivenessVSAvoidtissue tropism

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent applies parameter changes by modifying the capsid protein sequence through deamidation at specific positions (N57, N262, N384, N512) to alter the biochemical properties of the AAVrh75 capsid. This chemical modification changes the capsid's interaction with cellular receptors and immune components, thereby expanding tissue tropism and reducing preexisting immunity while maintaining the core functionality of the vector

Inventive Principle:

Principle #35Parameter changes

2Productivity

If AAV capsid proteins are produced from native sequences, then proper folding and assembly are achieved, but preexisting immunity and limited tissue targeting reduce transduction efficiency

Engineering Contradiction:

Improvetransduction efficiencyVSAvoidpreexisting immunity

Core Design Contradiction:

ProductivityVSObject-affected harmful factors

Solution Approach 1:

The patent applies local quality by making site-specific deamidation modifications at particular positions (N57, N262, N384, N512) within the capsid protein sequence while leaving the rest of the structure intact. This localized modification strategy allows the capsid to maintain its overall folding and assembly properties while acquiring new functional characteristics that evade preexisting immunity and enhance tissue-specific targeting

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent creates modified versions of the native AAVrh75 capsid protein by producing copies with deamidated amino acid residues at specific positions. These copied and modified capsid proteins are then expressed and assembled into viral particles that retain the basic structure and function of the original but possess improved transduction properties and reduced immunogenicity

Inventive Principle:

Principle #26Copying

Data Source

PatentUS20230407333A1AAV capsids and compositions containing same

Publication Date: 2023.12.21 THE TRUSTEES OF THE UNIV OF PENNSYLVANIA

AI summary

Novel AAV capsids and recombinant AAV vectors comprising the same are provided.