One in ten very premature infants — those born at less than 30 weeks gestation — are affected by retinopathy of prematurity (ROP), the leading cause of childhood blindness. During fetal development, the blood vessels of the eye’s retina — the tissue at the back of the eye that senses light and sends images to the brain — grow steadily out from the center of the eye toward its periphery, only reaching those edges when the fetus is close to normal-term gestation. If the baby is born early, this process is disrupted, which raises the risk for retinal detachment and consequent blindness.
The infection and inflammation experienced by many premature infants can impact normal retinal blood vessel growth. Importantly, so too can the relatively high oxygen levels that are commonly administered after delivery, explains Alison Chu, MD, a neonatologist and assistant professor of pediatrics at the David Geffen School of Medicine at UCLA.
Immediately following delivery, the amount of oxygen available to the newly born premature infant may suddenly increase to levels that are potentially toxic. This situation, known as hyperoxia, may lead to the narrowing of retinal blood vessels, or vascular attenuation. It is then often followed by local hypoxia, or low oxygen levels, which encourages the growth of new blood vessels but at an aberrant pace and pattern that may actually lead to retinal detachment.
In recent years, Dr. Chu and her colleagues have been taking a detailed look at the mechanisms behind these processes in both humans and animal models. The work could lead to the development of both preventive and therapeutic strategies to reduce risk of ROP development, and to improve long-term neurovision outcomes for premature babies.
Studies by Dr. Chu and others have shown several key genes that help drive retinopathy, including hypoxia-inducible factor one alpha (Hif1a) and vascular endothelial growth factor (VEGF).
“My group is particularly interested in studying a protein called epithelial membrane protein 2 (EMP2), which may regulate these vascular growth factors,” she says. The EMP2 gene is involved in regulating angiogenesis — the growth of new blood vessels. This normally vital role becomes problematic in ROP, however, where excessive blood vessel formation can lead to retinal detachment.
Indeed, in a recent paper published in the journal Investigative Ophthalmology & Visual Science, Dr. Chu and her colleagues showed that mice that were genetically engineered to not express the EMP2 gene (so-called “EMP2 knock-outs”) were protected against oxygen-induced retinopathy.
“We are interested in understanding how this could be translated to therapy in human babies,” she says. “Moreover, we are interested in understanding how retinopathy of prematurity may result in long-term adverse visual outcomes, by studying the vascular and neuronal changes both during active disease and in the long-term.”
To do so, Dr. Chu’s laboratory has teamed up with Tzung Hsiai, MD, PhD, a professor of bioengineering at the Samueli School of Engineering at UCLA. They are tracking the progression of oxygen-induced retinopathy in mice using advanced imaging techniques that offer deep and three-dimensional insight into disease progression in animal models.
In related work, Dr. Chu is collaborating with UCLA Health ophthalmologist Irena Tsui, MD, to use noninvasive imaging to study how structures in infants’ eyes are affected in real time by postnatal exposures to oxygen, or even treatments for ROP, in human babies.
Other projects are looking at the role of dietary factors and the microbiome — the vast collection of naturally occurring microbes that reside on and in, and work synergistically with, our bodies. Dr. Chu is working with Kara Calkins, MD, a neonatologist at UCLA Mattel Children's Hospital and UCLA Santa Monica Medical Center, and Elaine Hsiao, PhD, the De Logi Associate Professor in Biological Sciences at UCLA, to study “the role of polyunsaturated fatty acids and the microbiome in retinopathy of prematurity,” Dr. Chu says.
“This is really exciting work, because the intersection of nutrition and early development with the gut-brain axis is promising, with the potential to identify simple, cost-effective strategies which can be implemented worldwide to decrease ROP rates,” she says.
“As a field, we are understanding more and more how early life exposures affect later adult outcomes, and I think it's important to consider not only the short-term, but the long-term effects of the treatments we use in neonatology.”
Dr. Chu’s work has been supported by the National Institutes of Health, including the National Eye Institute and the Eunice Kennedy Shriver National Institute of Child Health and Human Development.