|
Retinopathy of prematurity (ROP) is a major cause of blindness in children. There are more than18,000 premature infants born in the United States every year who are at high risk for ROP. The disorder, which is characterized by initial lack of blood vessel growth, followed by abnormal and destructive blood vessel growth in the retina, was first described in 1942 but its cause was unknown.
In a study published in the May 1 electronic version of the Proceedings of the National Academy of Sciences (and in the May 8 print edition), researchers led by Lois EH Smith, MD, PhD, ophthalmologist at Children's Hospital Boston, along with Ann Hellstrom, MD, PhD and researchers from Queen Silvia Children's Hospital in Goteborg, Sweden, Beth Israel Deaconess Medical Center in Boston, and the National Institutes of Health, demonstrate that insulin-like growth factor 1 appears critical to blood vessel growth in the eye. Early replacement in premature infants might allow normal blood vessel growth and mitigate the later destructive retinal blood vessel growth that characterizes ROP, indicating it may prevent blindness in premature babies. Knowing that the greatest risk factors for development of ROP are low birthweight and gestational age, the researchers hypothesized that insulin-like growth factor 1 (IGF-1) might be implicated in ROP.
After birth, IGF-1 is not maintained at in utero levels due to the loss of IGF-1 provided by the placenta and the amniotic fluid. Researchers hypothesized that IGF-1 is critical to normal retinal vascular development and that a lack of IGF-1 in the early neonatal period is associated with lack of vascular growth and with subsequent proliferative ROP. To determine if IGF-1 is critical to normal blood vessel growth, the researchers first examined retinal blood vessel development in mice with the IGF-1 gene knocked out. The retinal blood vessels grew more slowly in the knockout mice than in those of normal mice, a pattern very similar to that seen in premature babies with ROP. Donald Senger, PhD, and other members of the research team next looked at how a loss of IGF-1 might cause the abnormal blood vessel growth. They determined that IGF-1 controls an important chemical signaling pathway--vascular endothelial growth factor (VEGF) activation of the cell survival pathway--that allows the survival of the cells making up the blood vessels. This finding explains how loss of IGF-1 could cause the disease by preventing the normal survival of vascular endothelial cells. Blood vessel growth is dependant on both IGF-1 and VEGF. In the absence of IGF-1 normally provided by the placenta and the amniotic fluid, blood vessel growth stops, and as parts of the eye mature they become oxygen starved, sending signals to increase VEGF. As the infant's organs and systems mature, IGF-1 levels rise and suddenly allow the VEGF signal to produce blood vessels. However, these are abnormal and can cause blindness.
To see if their observations in mice would hold true in infants, members of the research team at Queen Silvia Children's Hospital measured the IGF-1 levels in a group of premature infants to see if those who developed ROP had lower levels of IGF-1 than those who did not develop ROP. Babies without ROP (and normal retinal blood vessel growth) had significantly higher levels of IGF-1 than those who developed the disease (and had slow retinal blood vessel growth).
''This work has profound clinical implications because it describes a possible cause of retinopathy of prematurity and suggests that measurement of this growth factor could be used to predict which infants will develop the disease,'' says Smith. ''Moreover, it suggests that replacement of IGF-1 in premature infants might help to prevent the disease.''
Further clinical studies using IGF-1 replacement are being planned. (IGF-1 is an approved medication).
|
