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Jan 15, 2009
 |  BC Innovations  |  Targets & Mechanisms

Arresting infant retinopathy

Researchers at the Cleveland Clinic have found that activating hypoxia-inducible factor can prevent the progression of retinopathy in premature infants, which results in blindness if left unchecked. The findings, reported in the Proceedings of the National Academy of Sciences,open a new window for treating retinopathy of prematurity, although the challenge will be to pinpoint the proper time frame for administering HIF activators.

Retinopathy of prematurity (ROP), which affects more than 75% of severely premature infants, has two phases, which are based on the oxygen-regulated expression of VEGF.1 In the initial hyperoxic phase of the disease, decreases in VEGF lead to oxygen-induced vascular obliteration of the developing retina.

In the second, hypoxic, phase of the disease, the consequent lack of blood supply to the retina leads to vast areas of ischemia that prompt the overexpression of VEGF and erythropoietin (EPO). This results in pathologic neovascularization that causes bleeding and retinal detachment.

The Cleveland Clinic researchers sought to simulate hypoxia during the hyperoxic first phase by inhibiting hypoxia-inducible factor prolyl hydroxylase (EGLN2; HIF-PH; PHD). They hypothesized that the approach could prevent development of hypoxia-induced neovascularization and progression to the proliferative stage of the disease by promoting more robust upregulation of the proangiogenic molecules VEGF and EPO.2

PHD induces hydroxylation of hypoxia-inducible factor 1a (HIF1A; HIF-1a), which leads to the degradation and decreased stability of the HIF-1a transcription factor. Depending on the

concentration of oxygen within the cell, HIF-1a either is rapidly ubiquitinated and degraded or becomes stabilized to transcribe various hypoxia-responsive...

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