Rescuing Newborns' Vision
New approach leads to improvements in retinopathy
By Nancy Fliesler
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,”
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.
In further experiments, Smith and her team chemically blocked the
action of VEGF. This eliminated the problem of abnormal, excessive
vessel growth in the second phase of ROP, but it also worsened the
first phase of the disease by causing the loss of normal vessels.
Many years of follow-up experiments revealed that VEGF is actually
involved in two biochemical pathways. Targeting one pathway could
enhance normal, “good” vessel growth in the first phase
of ROP without affecting the other pathway, which was linked to the
abnormal second-phase growth. Smith’s team published these findings
last July in the Journal of Clinical Investigation.
| About 15 years ago, Smith decided that if
she needed to find a way to save these babies' failing vision..
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
“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
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
contact Brandt Henderson in the
Hospital Trust at (617) 355-5342