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Nov 05, 2009
 |  BC Innovations  |  Targets & Mechanisms

Norrin vs. VEGF

Two papers in Celldescribe a new signaling pathway that acts upstream of VEGF to control vascular development in the embryonic retina. The pathway is also present in adults, but the question is whether it's actually active and thus potentially targetable in diseases of retinal neovascularization, including diabetic retinopathy, retinopathy of prematurity and potentially wet age-related macular degeneration.

One study, from a team at The Johns Hopkins University School of Medicine, establishes how a secreted proangiogenic protein called Norrie disease pseudoglioma (NDP; Norrin) interacts with its receptor, frizzled homolog 4 (FZD4), to enable vascular growth during embryonic development.1 The other study, from a team at the Genentech Inc. unit of Roche, identifies an additional protein at the cell surface, tetraspanin 12 (TSPAN12), that helps FZD4 bind to Norrin.2

"The main finding is that the Norrin system is a novel signaling pathway with substantial effects on vascular development in mice and humans," said Jeremy Nathans, professor of molecular biology and genetics at Johns Hopkins and the lead author of one of the studies.

FZD4 is a transmembrane receptor present throughout the body during development and adulthood. In most tissues it responds to Wnt, a morphogenic protein that promotes cell division. Norrin is an alternative ligand for FZD4 present only in the retina and inner ear.

Norrin, FZD4 and TSPAN12 act together primarily in the retina and could thus be better targets for retina-specific anti-neovascular therapies than VEGF, which is active throughout the body. As transmembrane proteins, FZD4 and TSPAN12 are also potentially amenable to orally administered systemic small molecule therapeutics.

A fourth protein, low-density lipoprotein receptor-related protein 5 (LRP5), is part of the FZD4-TSPAN12 receptor complex. LRP5 knockouts appear to behave similarly to FZD4 knockouts.

The eyes have it

Previously,...

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