Editors' ChoicePharmacology

Preventing infant blindness

Sci. Signal.  10 May 2016:
Vol. 9, Issue 427, pp. ec108
DOI: 10.1126/scisignal.aag0791

Premature infants require oxygen to survive, but this treatment also causes damage to developing tissues, such as the retina and the lung. In the retina, hyperoxia causes loss of the vasculature and pathologic neovascularization, resulting in retinopathy of prematurity (ROP). Drugs that prevent the down-regulation of the hypoxia-stimulated transcription factor HIF-1α are being investigated to prevent the toxic effects of oxygen supplementation in premature infants. Hoppe et al. compared dimethyloxalylglycine (DMOG), which stabilizes HIF-1α primarily in the liver to stimulate the secretion of growth factors that promote angiogenesis and red blood cell development, and Roxadustat in mice. Both drugs protected mouse retinas from oxygen-induced retinopathy when administered systemically. The transcriptional signatures produced by each drug in the liver exhibited a ~50% (127/250) overlap, with a large group of genes (98/250) only responding to DMOG. Analysis of the transcripts encoding secreted products showed a high amount of similarity and included several hepatokines that could promote retinal protection. Compared with the transcriptional changes induced by DMOG in the retina (only five transcripts affected), Roxadustat triggered more transcriptional changes of which 2/32 were in common with DMOG and 27/32 were unique to Roxadustat. Experiments with mice lacking hepatic Hif1a demonstrated that systemic administration of DMOG primarily targeted the liver to provide protection from oxygen-induced retinopathy; whereas Roxadustat protected the liver-specific Hif1a-knockout mice from oxygen-induced retinopathy, indicating that Roxadustat directly targeted the retina. Roxadustat also protected the lung from oxygen-induced damage. Pharmacokinetic and dose-response analysis indicated that Roxadustat was more potent than DMOG, likely because Roxadustat exhibited both liver-dependent effects and direct effects on other tissues. Thus, premature infants requiring oxygen supplementation may benefit from intermittent (for example, weekly injections) Roxadustat therapy.

G. Hoppe, S. Yoon, B. Gopalan, A. R. Savage, R. Brown, K. Case, A. Vasanji, E. R. Chan, R. B. Silver, J. E. Sears, Comparative systems pharmacology of HIF stabilization in the prevention of retinopathy of prematurity. Proc. Natl. Acad. Sci. U.S.A. 113 E2516–E2525(2016). [PubMed]