Retinal Sequestering Compounds for Ocular Toxicity

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Solution Overview

Problem

All-trans-retinal, a retinoid metabolite produced during visual processing, is highly toxic at elevated levels and contributes to retinal toxicity, leading to diseases such as Stargardt macular dystrophy and age-related macular degeneration, due to its reactive aldehyde functionality.

Innovation Solution

Development of retinal sequestering compounds containing primary amines that can be delivered to and retained in the eye to modulate the visual cycle, specifically designed to form Schiff bases with all-trans-retinal, reducing its peak concentrations and toxicity without inhibiting essential retinoid metabolism enzymes.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If retinaldehyde is used to trigger light perception, then visual function is enabled, but retinal toxicity occurs due to reactive aldehyde functionality

Engineering Contradiction:

Improvevisual functionVSAvoidretinal toxicity

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent introduces retinaldehyde sequestering compounds as intermediary substances that selectively bind to free retinaldehyde molecules through Schiff base formation. These compounds act as mediators between the toxic retinaldehyde and retinal cells, capturing the aldehyde in a non-toxic complex form while allowing the visual cycle to continue functioning normally.

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The invention converts the harmful reactive aldehyde functionality into a beneficial therapeutic effect by utilizing the same chemical reactivity to form Schiff bases with sequestering compounds. The reactive retinaldehyde that causes toxicity is transformed into a stable complex that can be safely transported and eventually processed by cellular enzymes, turning the harmful property into the mechanism of protection.

Inventive Principle:

Principle #22Blessing in disguise (Convert harm into benefit)

2Reliability

If all-trans-retinal accumulates in ocular tissue, then visual chromophore regeneration is affected, but phototoxicity and retinal degeneration increase

Engineering Contradiction:

Improvevisual chromophore regenerationVSAvoidphototoxicity

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The patent extracts or removes free all-trans-retinal from the ocular tissue environment by introducing sequestering compounds that selectively bind to it. This extraction process reduces the concentration of toxic free retinaldehyde while maintaining the overall retinoid cycle function, as the sequestered retinal can still be processed by cellular enzymes like ALDH1A1.

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

The sequestering compounds serve as intermediary carriers that temporarily hold all-trans-retinal in a non-toxic complex form. This intermediary state allows the retinal to be transported through the ocular tissue without causing phototoxicity, and eventually delivered to enzymatic processing sites for conversion to less harmful metabolites.

Inventive Principle:

Principle #24Intermediary (Mediator)

3Object-affected harmful factors

If retinaldehyde clearance is enhanced, then toxicity is reduced, but visual cycle efficiency may be compromised

Engineering Contradiction:

Improveretinaldehyde toxicityVSAvoidvisual cycle efficiency

Core Design Contradiction:

Object-affected harmful factorsVSProductivity

Solution Approach 1:

The patent applies partial action by introducing sequestering compounds at specific concentrations and locations within the ocular tissue, rather than attempting to completely eliminate all retinaldehyde. This partial sequestration is sufficient to reduce toxicity to acceptable levels while leaving enough free retinaldehyde available to maintain normal visual cycle flux and chromophore regeneration.

Inventive Principle:

Principle #16Partial or excessive action

Solution Approach 2:

The invention changes the chemical state parameters of retinaldehyde by forming reversible Schiff base complexes with sequestering compounds. This parameter change (from free aldehyde to complexed form) reduces reactivity and toxicity while allowing dynamic equilibrium to maintain adequate free retinaldehyde levels for visual function, thus preserving visual cycle efficiency.

Inventive Principle:

Principle #35Parameter changes

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 retinal sequestering compounds effectively reduce the levels of free all-trans-retinal in ocular tissue, mitigating retinal degeneration while maintaining normal visual chromophore regeneration, thus preventing conditions like macular degeneration and retinal phototoxicity.

Implementation Method 1

therapeutic retinal sequestering compounds that include primary amines have been identified in the Example below that can be delivered to and retained in the eye to modulate the visual (retinoid) cycle

Methodology Applied

Scientific EffectSchiff base formation: Chemical Bonding

Data Source

PatentUS12144788B2Visual cycle modulators

Publication Date: 2024.11.19 CASE WESTERN RESERVE UNIV

AI summary

A method of treating an ocular disorder in a subject in need thereof includes administering to the subject a therapeutically effective amount of a retinal sequestering compound of formula (I).