rAAV.PHP.B Vector Transducing Cochlear Cells for Hearing Loss

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Solution Overview

Problem

Current gene therapy approaches for treating hereditary hearing loss, such as Usher syndrome, face challenges in effectively targeting and transducing cochlear cells across species, including humans, due to limited vector efficacy and postnatal hair cell degeneration, which complicates clinical translation.

Innovation Solution

Development of a recombinant adeno-associated virus (rAAV) vector, rAAV.PHP.B, capable of delivering transgenes to all cochlear cells, including inner and outer hair cells, and fibrocytes across multiple species, using a capsid protein with enhanced tropism for the ear and eye, along with specific promoters to express clarin-1 or GJB2 proteins.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Adaptability or versatility

If conventional AAV vectors are used for gene therapy, then some cochlear cells can be transduced, but not all cochlear cells are effectively targeted

Engineering Contradiction:

Improvetransduction coverageVSAvoidgene therapy efficacy

Core Design Contradiction:

Adaptability or versatilityVSReliability

Solution Approach 1:

The patent modifies the capsid protein parameters of AAV vectors to create variants with enhanced cochlear tropism. By changing physical-chemical properties of the viral capsid, the vector achieves universal transduction of all cochlear cell types including hair cells, supporting cells, and neurons, resolving the limitation of partial cell targeting

Inventive Principle:

Principle #35Parameter changes

2Reliability

If gene therapy is performed in neonatal mice, then hearing rescue is achieved, but translational potential to humans is unknown

Engineering Contradiction:

Improvehearing rescue efficacyVSAvoidcross-species applicability

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent develops AAV vectors with universal cochlear transduction capability that functions across multiple species including mice, non-human primates, and potentially humans. The modified capsid provides species-independent tropism for cochlear cells, enabling the same vector to achieve hearing rescue in diverse mammalian models

Inventive Principle:

Principle #6Universality (Multi-functionality)

3Loss of time

If postnatal gene therapy is performed, then treatment can be applied later in development, but hair cell targets may have already degenerated

Engineering Contradiction:

Improvetreatment timing flexibilityVSAvoidtarget cell availability

Core Design Contradiction:

Loss of timeVSReliability

Solution Approach 1:

The patent enables gene delivery to cochlear cells at postnatal stages by using AAV vectors with enhanced tropism that can effectively transduce hair cells and supporting cells even after birth. This preliminary establishment of functional gene expression before complete hair cell degeneration occurs allows for effective treatment timing

Inventive Principle:

Principle #10Preliminary action

Data Source

PatentUS12054724B2AAV vectors encoding clarin-1 or GJB2 and uses thereof

Publication Date: 2024.08.06 THE GENERAL HOSPITAL CORP

AI summary

Aspects of the disclosure relate to compositions and methods useful for treating hereditary hearing loss, for example, Usher syndrome type 3A or nonsyndromic hearing loss and deafness (DFNB1). In some embodiments, the disclosure provides isolated nucleic acids, vectors, and rAAV.9.PHP.B comprising a transgene encoding a Clarin-1 or a GJB2, and methods of treating hearing loss using the same.