Engineered rAAV Capsids for Ocular Tissue Targeting

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Solution Overview

Problem

There is a need for recombinant adeno-associated viruses (rAAVs) with enhanced tropism for ocular tissues to effectively deliver therapeutics for treating ocular disorders, as existing methods have limited success in targeting and transducing ocular tissues such as the retina and RPE-choroid tissue.

Innovation Solution

Development of rAAV particles with capsid proteins that specifically target ocular tissues, including the use of engineered capsids like AAV3B, AAVrh.73, AAVhu.26, and AAV9.S454.TFR3, which enhance cellular uptake and integration in ocular tissues, allowing for the delivery of therapeutic transgenes via intravitreal, suprachoroidal, or intracameral administration.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional AAV vectors (e.g., AAV2) are used for gene delivery, then long-term targeted gene expression is achieved, but tropism for ocular tissues is limited

Engineering Contradiction:

Improvelong-term targeted gene expressionVSAvoidtropism for ocular tissues

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent applies local quality by engineering specific capsid variants (AAV3B, AAVrh.73, AAVhu.26, AAV9.S454.TFR3) with modified surface properties that specifically recognize and bind to ocular tissue receptors. This localized modification of capsid properties enables selective targeting of ocular tissues while preserving the overall AAV vector structure and long-term gene expression capability

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent employs parameter changes by altering capsid protein sequences and surface characteristics to enhance ocular tissue affinity. Specific amino acid modifications in the capsid structure change the binding parameters to match ocular tissue receptors, thereby improving tropism while maintaining vector functionality

Inventive Principle:

Principle #35Parameter changes

2Productivity

If rAAV vectors with enhanced ocular tissue tropism are developed, then transduction efficiency in ocular tissues is improved, but vector design complexity increases

Engineering Contradiction:

Improvetransduction efficiency in ocular tissuesVSAvoidvector design complexity

Core Design Contradiction:

ProductivityVSDevice complexity

Solution Approach 1:

The patent applies segmentation by separating the AAV vector into distinct functional components: the engineered capsid protein responsible for ocular targeting and the therapeutic transgene payload. This modular design allows independent optimization of targeting properties through capsid engineering while keeping the gene delivery mechanism standardized

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent achieves universality by creating capsid variants that maintain multiple functions: ocular tissue targeting, cellular entry, and long-term gene expression. The engineered capsids serve as multi-functional platforms that combine targeting specificity with the established safety and efficacy profile of recombinant AAV vectors

Inventive Principle:

Principle #6Universality (Multi-functionality)

Data Source

PatentUS20230381341A1Adeno-associated viruses for ocular delivery of gene therapy

Publication Date: 2023.11.30 REGENXBIO INC

AI summary

The present invention relates to recombinant adeno-associated viruses (rAAVs) having capsid proteins that have a tropism for ocular tissue. The rAAVs have capsids that have enhanced or increased transduction of ocular tissues as compared to reference rAAVs. Such rAAVs may be useful in delivering transgenes encoding therapeutic proteins for the treatment of ocular disease.