Recombinant AAV-S Capsid for Usher Syndrome Gene Therapy

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Solution Overview

Problem

Current adeno-associated virus (AAV)-based gene therapy lacks effective serotypes that can transduce all cochlear and retina cells, posing significant challenges for clinical translation in treating hereditary hearing and vision loss conditions like Usher Syndrome, Type 3A.

Innovation Solution

Development of a recombinant adeno-associated virus (rAAV) with an AAV-S capsid protein and a transgene encoding the clarin-1 protein, specifically designed to target inner ear and eye cells, using AAV-S capsid protein variants that efficiently deliver genetic material to a wide range of cochlear and retinal cells across multiple species.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional AAV serotypes are used for gene therapy, then the vector can be produced and administered, but it fails to transduce all cochlear and retinal cells effectively

Engineering Contradiction:

Improvetransduction efficiencyVSAvoidcell type coverage

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent develops AAV-S capsid protein variants that can transduce multiple cell types across different tissues (cochlear cells including hair cells and supporting cells, and retinal cells including photoreceptors and RPE cells), making a single vector system universally effective for treating Usher syndrome type 3A in both hearing and vision pathways

Inventive Principle:

Principle #6Universality (Multi-functionality)

Solution Approach 2:

The patent employs capsid protein variants with at least 80% identity to AAV-S amino acid sequence, exploring sequence variations to optimize transduction efficiency across different cell types while maintaining the core functionality of the AAV-S capsid structure

Inventive Principle:

Principle #35Parameter changes

2Reliability

If AAV-based gene therapy is developed for hereditary hearing and vision loss, then treatment approach is established, but significant challenges remain for clinical translation

Engineering Contradiction:

Improvetreatment efficacyVSAvoidclinical translation feasibility

Core Design Contradiction:

ReliabilityVSEase of manufacture

Solution Approach 1:

The patent performs preliminary validation of AAV-S capsid variants in animal models (including mice and non-human primates) to demonstrate robust and durable rescue of hearing and vision before clinical translation, establishing proof of concept and safety profile in advance

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The patent uses auditory brainstem response and distortion product otoacoustic emission tests to monitor and evaluate the efficacy of gene therapy treatment in animal models, providing feedback on treatment effectiveness to guide further development and optimization

Inventive Principle:

Principle #23Feedback

Data Source

PatentUS12129287B2Recombinant adeno associated virus encoding clarin-1 and uses thereof

Publication Date: 2024.10.29 THE GENERAL HOSPITAL CORP

AI summary

Aspects of the disclosure relate to compositions and methods for treating hereditary hearing loss and/or vision loss, for example, due to Usher syndrome, Type 3A. In some embodiments, the disclosure provides a recombinant adeno-associated virus comprising: (i) an AAV-S capsid protein, and (ii) an isolated nucleic acid comprising a transgene (e.g., a transgene for expressing a clarin-1 protein). The present disclosure also provides methods of treating hereditary hearing loss and/or vision loss (e.g., Usher Syndrome, Type 3A) using the same.