Otoferlin Gene Segmentation for Hearing Restoration

Solution Overview

Problem

Current treatments for hearing loss, particularly non-syndromic sensorineural hearing loss, lack effective methods for prevention or reversal, relying mainly on hearing amplification and cochlear implantation with limited regenerative approaches.

Innovation Solution

A composition of two different nucleic acid vectors, each encoding a portion of the otoferlin protein, undergoes concatemerization or homologous recombination to form a full-length otoferlin protein in mammalian cells, potentially treating non-syndromic sensorineural hearing loss by enhancing inner hair cell function.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional hearing treatments (amplification and implantation) are used, then hearing function can be partially restored, but they cannot prevent or reverse the underlying cellular damage and have limited regenerative capabilities

Engineering Contradiction:

Improvehearing function restorationVSAvoidregenerative capability

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent segments the full-length otoferlin protein coding sequence into multiple smaller cDNA fragments, each contained within separate viral vectors. This segmentation allows the vectors to individually target and deliver specific portions of the otoferlin gene to inner hair cells, which then assemble the complete functional protein through natural cellular mechanisms, enabling genetic regeneration without requiring a single complex vector system

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent uses viral vectors as intermediary carriers to deliver the otoferlin cDNA fragments into inner hair cells. These viral intermediaries facilitate the transfer of genetic material across the cell membrane, enabling the introduction of therapeutic genes that would otherwise be unable to enter the cells directly, thus bridging the gap between external treatment and internal cellular repair

Inventive Principle:

Principle #24Intermediary (Mediator)

2Manufacturing precision

If a single viral vector is used to deliver the complete otoferlin gene, then the full-length protein can be expressed, but the vector size exceeds the packaging capacity of available viral vectors

Engineering Contradiction:

Improvefull-length protein expressionVSAvoidvector packaging capacity

Core Design Contradiction:

Manufacturing precisionVSDevice complexity

Solution Approach 1:

The patent divides the large otoferlin coding sequence into multiple smaller cDNA fragments that each fit within the packaging capacity of standard viral vectors. These segmented genetic pieces are delivered separately by multiple vectors, which then reassemble into the complete functional gene within the target cell, bypassing the packaging size limitation while achieving full-length protein expression

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent employs a nested structure where multiple viral vectors, each containing a portion of the otoferlin gene, work together in a coordinated manner. The vectors are administered as a combination therapy, with each vector nesting its specific genetic fragment within its capsid, and the cellular machinery nesting these fragments together to form the complete functional gene product

Inventive Principle:

Principle #7Nested doll (Nesting)

3Reliability

If genetic therapy is used to restore otoferlin function, then inner hair cell function can be improved, but the delivery of genetic material to inner ear cells presents significant technical challenges

Engineering Contradiction:

Improveinner hair cell functionVSAvoidgenetic material delivery

Core Design Contradiction:

ReliabilityVSEase of manufacture

Solution Approach 1:

The patent uses viral vectors as intermediary delivery vehicles to transport otoferlin cDNA fragments into inner hair cells. These viral intermediaries naturally possess the ability to infect and deliver genetic material to mammalian cells, overcoming the barrier of difficult genetic delivery to the inner ear while maintaining the therapeutic benefit of otoferlin restoration

Inventive Principle:

Principle #24Intermediary (Mediator)

Applied Scientific Principles

This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.

Function Achieved in This Case

The approach aims to increase expression of a full-length otoferlin protein in inner hair cells, potentially restoring hearing by improving cellular function and regenerative capabilities within the inner ear.

Implementation Method 1

A composition of two different nucleic acid vectors, each encoding a portion of the otoferlin protein, undergoes concatemerization or homologous recombination to form a full-length otoferlin protein in mammalian cells

Methodology Applied

Scientific EffectConcatemerization:

Implementation Method 2

A composition of two different nucleic acid vectors, each encoding a portion of the otoferlin protein, undergoes concatemerization or homologous recombination to form a full-length otoferlin protein in mammalian cells

Methodology Applied

Scientific EffectHomologous recombination:

Implementation Method 3

The approach aims to increase expression of a full-length otoferlin protein in inner hair cells, potentially restoring hearing by improving cellular function and regenerative capabilities within the inner ear

Methodology Applied

Scientific EffectGene expression:

Data Source

PatentUS20220040327A1Compositions and methods for treating non-age-associated hearing impairment in a human subject

Publication Date: 2022.02.10 AKOUOS INC

AI summary

Provided herein are compositions that include at least two different nucleic acid vectors, where each of the at least two different vectors includes a coding sequence that encodes a different portion of an otoferlin protein, and the use of these compositions to treat hearing loss in a subject.