Damming a Cascade to Blindness

Scientists may have found a novel way to block a chain of molecular signals that leads to the most common form of blindness. A compound that jams the receptor for a signaling molecule successfully prevented half the rampant blood vessel growth in the eyes of newborn mice. The condition can blind prematurely born infants, people with diabetes, and the elderly, a team reports in this month's Nature Medicine.

When the eyes are oxygen-starved, cells that line the retina send out chemical distress signals. One such alarm, a molecule known as vascular endothelial growth factor (VEGF), tries to save the day by sprouting new blood vessels. Ultimately, though, this bungles the rescue by sparking the formation of leaky vessels--a general condition known as hypoxia-induced proliferative retinopathy. Probing this chain of events, ophthalmologist Lois Smith and her colleagues at Harvard Medical School and Children's Hospital in Boston examined the role of a signaling molecule called insulinlike growth factor-1 (IGF-1), which had been linked to VEGF action in both mice and humans.

Smith began by mimicking retinopathy in newborn mice. She placed 7-day-old pups along with their nursing mothers into chambers infused with 70% oxygen and then removed the animals after 5 days. As with premature babies, the lower oxygen concentration deprived the infants' eyes of oxygen. The researchers then gave the newborns daily injections of either a peptide known to block IGF-1's receptor or a control. Five days later, blood vessel growth in the eyes of mice given the inhibitor was half that of the control animals.

The mechanism isn't direct. Rather than blocking the VEGF production, the compound prevents the IGF-1 receptor from triggering the VEGF receptor, which normally passes on the command to make new blood vessels. The reason that some blood vessels still grew in the experimental animals, Smith suggests, is that signaling compounds other than IGF-1 may still be operating.

"This study is intriguing and shows that there is some interaction between IGF-1 and VEGF signaling pathways," says ophthalmologist Peter Campochiaro at the Johns Hopkins School of Medicine in Baltimore, a long-time retinopathy researcher. But he believes that IGF-1 might not be the best receptor to target. Campochiaro and his colleagues plan to begin clinical trials on an antagonist of the VEGF receptor that is 100% effective at blocking VEGF. It's not yet clear whether this more drastic approach will be safe in people. "What we are trying to do is to look at more complicated interactions so that we can better modulate these pathways for clinical purposes," Smith says.