HIF-1α Stabilization for Retinal Vessel Protection in Premature Infants

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Solution Overview

Problem

Current treatments for retinopathy of prematurity (ROP) do not effectively inhibit the destruction of retinal blood vessels, and existing methods to address oxygen-induced vascular obliteration and hypoxia-induced neovascularization are inadequate, leading to potential childhood blindness in premature infants.

Innovation Solution

Stabilization of hypoxia-inducible factor 1α (HIF-1α) using systemic PHD inhibitors, such as FG-4592, which is administered to premature infants during hyperoxia to prevent the destruction of retinal blood vessels and associated retinopathy, while allowing necessary oxygen supplementation.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If oxygen supplementation is provided to premature infants to maintain life, then survival is improved, but retinal vascular destruction and ROP develop

Engineering Contradiction:

ImprovesurvivalVSAvoidretinal vascular destruction

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent introduces HIF-1α stabilization as an intermediary mechanism that mediates between oxygen supplementation and retinal protection. By stabilizing HIF-1α during hyperoxia, the compound enables the retinal vasculature to withstand oxygen-induced stress without requiring reduced oxygen supply, thus resolving the contradiction between survival and retinal protection

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The patent changes the biochemical parameter of HIF-1α stability through PHD inhibition. This parameter change allows the retinal vasculature to maintain its protective response during hyperoxia, transforming the harmful effect of oxygen into a non-damaging condition while preserving the benefit of oxygen supplementation for survival

Inventive Principle:

Principle #35Parameter changes

2Object-generated harmful factors

If VEGF and HIF-1α inhibitors are used to treat ROP, then neovascularization is reduced, but retinal blood vessel destruction is not inhibited

Engineering Contradiction:

ImproveneovascularizationVSAvoidretinal blood vessel destruction

Core Design Contradiction:

Object-generated harmful factorsVSObject-affected harmful factors

Solution Approach 1:

Instead of inhibiting HIF-1α (conventional approach), the patent stabilizes HIF-1α during hyperoxia. This inversion of the conventional strategy transforms the mechanism of action from suppressing the hypoxic response to enhancing it during oxygen exposure, thereby preventing vascular destruction while avoiding neovascularization

Inventive Principle:

Principle #13The other way round (Inversion)

Solution Approach 2:

The patent applies preliminary anti-action by stabilizing HIF-1α before retinal vascular destruction occurs. By pre-stabilizing HIF-1α during hyperoxia, the compound prevents the harmful effect of oxygen-induced vascular obliteration before it can manifest, rather than treating the consequence afterward

Inventive Principle:

Principle #9Preliminary anti-action

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 stabilization of HIF-1α with FG-4592 effectively inhibits the destruction of retinal blood vessels and prevents the progression of ROP, preserving retinal vessels and reducing oxygen-induced damage without restricting oxygen supply to premature infants.

Implementation Method 1

HIF-1α and, in particular, hepatic HIF-1α, can be stabilized by inhibition of hypoxia-inducible factor prolyl hydroxylase (PHD) using system PHD inhibitors

Methodology Applied

Scientific EffectProlyl hydroxylase inhibition: Enzyme

Data Source

PatentUS9820981B2Treatment of retinopathy of prematurity (ROP)

Publication Date: 2017.11.21 THE CLEVELAND CLINIC FOUND

AI summary

Disclosed herein are methods of treating retinopathy of prematurity (ROP) in a premature and/or low birth weight infant in need thereof, comprising administering to the infant an effective amount of a compound represented by Structural Formula I, Structural Formula la or Structural Formula II described herein, or a pharmaceutically acceptable salt thereof. Also disclosed herein are methods of inhibiting the destruction of retinal blood vessels in a premature and/or low birth weight infant in need thereof, comprising administering to the infant an effective amount of a compound represented by Structural Formula I, Structural Formula la or Structural Formula II, or a pharmaceutically acceptable salt thereof. Also disclosed herein are methods of treating hyperoxia in a premature and/or low birth weight infant in need thereof, comprising administering to the infant an effective amount of a compound represented by Structural Formula I, Structural Formula la or Structural Formula II, or a pharmaceutically acceptable salt thereof. By using the methods disclosed herein, particularly when an infant is hyperoxic, oxygen toxicity to the retina of the eye can be inhibited without restricting oxygen supplementation, which is often necessary to sustain the life of premature infants.