Rod Photoreceptor Gene Therapy for Cone Dysfunction

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Solution Overview

Problem

Current treatments for vision disorders primarily focus on restoring cone function, which is ineffective in conditions where cones are severely or entirely lost, but some rod photoreceptors remain functional, limiting the effectiveness in addressing cone dysfunction and macular degeneration.

Innovation Solution

The use of an adeno-associated virus (AAV) vector expressing light-sensitive proteins like ArchT, R9AP, or iC1C2 in rod photoreceptors to enhance their sensitivity and response speed, allowing them to function more like cones and compensate for cone dysfunction, thereby improving vision.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If treatments focus on restoring cone function, then cone-mediated vision is improved, but vision cannot be restored in conditions where cones are severely or entirely lost

Engineering Contradiction:

Improveeffectiveness of vision treatmentVSAvoidapplicability to different vision conditions

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

Instead of attempting to restore function to damaged or absent cones, the invention inverts the approach by enhancing the function of remaining rod photoreceptors. By introducing light-sensitive proteins (rhodopsin, cone opsins) and modifying rod characteristics through gene therapy, the treatment makes rods respond more like cones, thereby compensating for cone loss and enabling vision restoration in conditions where traditional cone-targeted therapies would fail.

Inventive Principle:

Principle #13The other way round (Inversion)

2Reliability

If rod photoreceptors are used to compensate for cone loss, then vision can be improved in cone dysfunction conditions, but rods have inherently slower response speed and lower light saturation threshold compared to cones

Engineering Contradiction:

Improvevision restoration capabilityVSAvoidphotoreceptor response speed

Core Design Contradiction:

ReliabilityVSSpeed

Solution Approach 1:

The invention changes key parameters of rod photoreceptor function by introducing exogenous light-sensitive proteins and modifying cellular characteristics through gene therapy. By expressing cone opsins (SWC, LWC) in rods and adjusting phototransduction properties, the treatment increases light saturation thresholds and accelerates response kinetics, making rods capable of functioning at higher light levels with faster response times more comparable to native cone performance.

Inventive Principle:

Principle #35Parameter changes

3Illumination intensity

If rods are enhanced to respond to brighter light, then they can compensate for cone dysfunction in daylight conditions, but their sensitivity to dim light may be reduced

Engineering Contradiction:

Improvelight response rangeVSAvoidscotopic vision sensitivity

Core Design Contradiction:

Illumination intensityVSReliability

Solution Approach 1:

The invention creates multi-functional photoreceptor cells that can operate across a broader range of light conditions. By introducing multiple opsin types (rhodopsin for dim light, cone opsins SWC and LWC for brighter light) into rod photoreceptors, the treatment enables single cells to perform both scotopic and photopic functions, thereby maintaining sensitivity to dim light while gaining the ability to respond effectively to brighter daylight conditions.

Inventive Principle:

Principle #6Universality (Multi-functionality)

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

This approach enables rods to respond to a broader range of light intensities and respond more quickly, effectively compensating for cone dysfunction and improving visual acuity and sensitivity, particularly in conditions like achromatopsia and age-related macular degeneration.

Implementation Method 1

The use of an adeno-associated virus (AAV) vector expressing light-sensitive proteins like ArchT, R9AP, or iC1C2 in rod photoreceptors

Methodology Applied

Scientific EffectGene therapy:

Implementation Method 2

Expression of a light-sensitive or light-gated G-coupled membrane protein, ion channel, ion pump or ion transporter in the rod

Methodology Applied

Scientific EffectLight-driven proton pump:

Implementation Method 3

R9AP tethers the complex to the disc membrane at the photoreceptor outer segment where the phototransduction signalling also takes place

Methodology Applied

Scientific EffectPhototransduction:

Data Source

PatentEP3261679B1Gene therapy to improve vision

Publication Date: 2023.05.03 UCL BUSINESS LTD

Figure 1a~1d
Figure 2a~2d
Figure 2e~2f

AI summary

The invention relates to the use of gene therapy vectors to improve vision by introducing into healthy rod photoreceptor cells of a patient suffering from cone photoreceptor dysfunction and/or degeneration a nucleic acid encoding a gene product that is light-sensitive and/or that modulates endogenous light-sensitive signalling in a photoreceptor cell, such that the range of light intensities to which the rod photoreceptor responds is extended and/or the speed at which the rod photoreceptor responds to light is increased.