 |
|
 |
|
|
|
|
 |
|
Rescuing Newborns' Vision New approach leads to improvements in retinopathy treatment
|
|
Lois Smith examines Jared Stern for retinopathy of prematurity. Despite the fact that he was several months premature, Jared was not diagnosed with ROP. Photo Paula Lerner ©2004 |
Pediatric ophthalmologist Lois Smith, MD, PhD, has cared for many extremely premature babies, some weighing less than one pound. Not only do these vulnerable infants have life-threatening health problems, but many also go blind from a condition related to their prematurity. About 15 years ago, Smith decided that she needed to find a way to save these babies' vision. The babies suffered from retinopathy of prematurity, or ROP. First recognized in the 1940s, ROP is a disease of the retina, or the nerve tissue in the eye that converts light into signals that the brain perceives as images. Before going into medicine, Smith had a PhD in chemistry, so she decided to return to the lab and search for the root causes of the disease. As a result, the first new treatment for ROP in decades is entering clinical trials – and it’s based on a hormone naturally produced by the body. ROP has two phases. First, in some premature babies, the blood vessels that feed the infants’ tiny retinas stop growing and even begin to disappear. “There’s no blood supply, so the retina becomes oxygen starved,” Smith explains. “It sends out signals screaming for oxygen, causing an outpouring of new blood- vessel formation.” Unfortunately, th new vessels are malformed, leaky and excessive in number, and form a rigid band of tissue that actually pulls the retina away from its supporting layer. This is the second phase of ROP. The retinal detachment prevents nerve signals from being transmitted, causing black spots in the vision and ultimately complete blindness. In the 1940s, no one knew exactly why all this happened, but one ROP risk factor was known: excessive oxygen use in premature babies seemed to make the retina “think” that it had more than enough blood vessels and start pruning the vessels back, causing the eyes to become oxygen starved. Over the ensuing decades, doctors reduced and refined their use of supplemental oxygen, and rates of ROP declined. But in recent years, as technological advances have saved the lives of very-low-birthweight infants, ROP has made a comeback: Extreme prematurity, it turns out, is a risk factor too. “Some babies now survive even between 22 and 23 weeks’ gestation,” notes Smith. “The more premature the baby, the higher the incidence of the disease.” As many as 95 percent of babies born at 23 weeks develop ROP, as compared with 10 percent of those born at 32 weeks. Treatments do exist for ROP, but Smith terms them “crude.” Using a laser or a freezing probe, doctors destroy part of the retina – the part that is screaming for new blood vessels – in an effort to halt disease progression. This reduces rates of blindness by about 25 percent, but doesn’t improve the chances of good vision and leaves babies with tunnel vision. “We wanted to go in earlier to prevent retinal damage before it starts,” says Smith. Smith’s quest began by looking at the first ROP risk factor, oxygen delivery. She worked with newborn mice, which, like premature babies, have only partially developed retinas. When the mice were put into oxygen, their retinal blood vessels stopped growing or disappeared. Moreover, retinal levels of a growth chemical, called vascular endothelial growth factor (VEGF), plummeted. But when the mice were brought back into normal room air, VEGF levels surged and blood vessels resumed normal growth.
But even as this VEGF work was going on, Smith read a 50-year-old case history that took her research in an entirely new direction. In 1953, a doctor named J.E. Poulsen had a patient with diabetes who developed severe diabetic retinopathy, which, like ROP, is marked by a loss of retinal vessels followed by abnormal vessel growth and retinal detachment. The unfortunate woman delivered a baby and suffered a severe childbirth complication: a stroke that destroyed her pituitary gland. As a result, she lost all the hormones that the pituitary normally produces and became very ill. Oddly, though, her diabetic retinopathy disappeared. “Because of this case,” Smith notes, “ophthalmologists used to take out the pituitary in patients who had really bad diabetic retinopathy – which is pretty draconian.” A follow-up study of 115 patients in 1987 confirmed that almost all had regression of their retinopathy. People thought this had something to do with the loss of growth hormone (GH), “but everybody forgot about it,” says Smith, “because right after that happened, this awful treatment was replaced by a laser treatment.” But Smith, intrigued, decided to investigate the role of GH, the major growth hormone in the body. She began working with giant mice, which produced too much GH, and dwarf mice, which produced too little. This work gradually led her to another compound known as insulin-like growth factor I, or IGF-I, which works in concert with GH and is important for growth and development of the brain, lungs, intestines and other organs. Working with a new type of mouse, one unable to produce IGF-I, “we found out that IGF-I was really important for normal vessel growth,” Smith says. “If IGF-I is low, vessels don’t grow.” The research moved quickly into humans. Smith’s group found that in the third trimester of pregnancy, IGF-I levels in the fetus rise markedly because they get the factor from the mother in utero. But if babies are born very prematurely, this supply is cut off, and their levels of IGF-I begin to decline. This finding prompted Smith and Ann Hellström, MD, PhD, a collaborator in Sweden, to follow 80 babies born at 24 to 32 weeks’ gestation. The babies had their blood drawn weekly to measure IGF-I levels, from birth until hospital discharge. IGF-I level at the gestational age of 30 to 33 weeks was the most important predictor of whether a preterm baby would develop ROP. In babies who developed ROP, IGF-I levels never rose to the level they would have achieved at 30 to 33 weeks in utero. In contrast, infants without ROP did achieve normal or near-normal levels of IGF-I; these babies managed to make enough IGF-I soon enough after birth to head off the disease. “It looks like having really low levels of IGF-I can prevent normal blood vessel growth,” says Smith. “This precipitates the second phase of retinopathy, where blood vessels proliferate abnormally.” The study, published in the November issue of Pediatrics, also found that preterm babies with low IGF-I levels were more likely to suffer other serious complications: necrotizing enterocolitis, a disease in which the bowel becomes leaky, so food can’t be digested; bronchopulmonary dysplasia, a lack of growth of the lungs; and intraventricular hemorrhage, in which immature, fragile blood vessels in the brain burst and bleed, damaging brain tissue and sometimes causing the baby’s head to expand abnormally. Smith and Hellström are now beginning a Phase I clinical trial in Sweden to see if supplementing IGF-I in premature newborns will prevent ROP and these other diseases. Starting at birth, the babies will receive IGF-I intravenously in very small amounts until they can make enough on their own to maintain the levels they would have had in utero. This may take just a few days, or a few weeks, depending on the baby’s need. If all goes well, this trial will lead to an expanded, multicenter trial in Sweden and the U.S. “We’re asking, ‘Can we view some aspects of prematurity as an IGF-I deficiency, just as diabetes is an insulin deficiency?’ ” says Smith. While this trial’s goal is prevention, Smith plans a second trial in newborns to see if blocking VEGF action with drugs in the second phase of ROP will reverse or at least arrest the disease. This trial, probably several years away, will proceed cautiously, because blocking VEGF too much may be counterproductive, preventing normal blood vessel growth and stunting vessel growth elsewhere in the body. Initially, the trial will enroll only children with ROP who aren’t responding to laser treatment. The anti-VEGF agents would be administered only in the eye, not injected into the blood as with IGF-I. Smith guesses that many chemical factors besides IGF-I and VEGF are involved in ROP. “In science, you have to look at one thing at a time,” she says. “You try to find pathways that you can alter to make a difference, and you just keep on pushing. It helps to keep one goal in mind so you know what you want to do. And the goal has always been, ‘How can we prevent this disease?’ ” To support ophthalmology research
at Children’s, |
ROP illustrated
Retinopathy
of prematurity is
ROP through an
|
