John Penn, Ph.D., vice chair of the Department of Ophthalmology and Visual Sciences at Vanderbilt, is seeking to change the way retinopathy of prematurity (ROP), the leading cause of childhood blindness worldwide, is treated.
But in order to effect a change in the way neonatologists treat the disorder, he must first convince his colleagues that general dogma regarding the pathogenesis of the disease is flawed.
In a recent paper in the New England Journal of Medicine (NEJM), Penn, along with M. Elizabeth Hartnett, M.D., from the John A. Moran Eye Center in Salt Lake City, refute the relevance of experimental models still used to study ROP pathogenesis, which call for constant exposure to high oxygen levels that mimic treatments administered to premature infants several decades ago.
“Early experiments from the 1950s taught us a lot about the dangers of extended exposures to highly elevated oxygen that were used to treat premature infants at that time,” said Penn. “However, as we’ve developed better tools for neonatal care, the nature of ROP has changed drastically.
“It’s unfortunate that we continue to train our basic biomedical scientists and clinicians using the same or similar models that are now clinically irrelevant. It causes our trainees to misunderstand the pathogenesis of ROP rather than understand it better.”
Based on Penn’s work at the Vanderbilt Eye Institute, it has been recognized that fluctuating bloodstream oxygen, rather than simply high levels of oxygen in the blood, is an important risk factor for ROP, as well as a host of other circumstances and conditions.
Experimental therapies that were devised using the extremely high constant oxygen models are predicated on faulty premises, Penn said.
“Early investigators exposed animals to a high-oxygen milieu similar to that used in the treatment of preterm infants at the time, but they did not consider the fact that the newborn animals they studied had healthy lung function,” state the authors. “In addition, the oxygen levels used then differ considerably from those currently used in preterm infants.”
Penn said that the problem with using extremely high and constant oxygen levels to study ROP is that those conditions cause the destruction of existing retinal blood vessels, and with no evidence of that occurring in ROP it is an impediment to developing new therapeutic strategies.
“Trainees are studying the phenomenon of blood vessel destruction as if it were a fundamental part of the human disease, when in fact it is not now and probably hasn’t been for a long, long time. This misconception has gone on for decades, despite the fact that there is now ample clinical evidence to refute it,” Penn said.
New and improved models are leading to a better understanding of the disorder as well as a more rational development of therapeutic strategies to treat ROP.
Penn and Hartnett, widely recognized experts in the field of ROP pathogenesis, submitted the medical progress report upon invitation from the NEJM.
“It was important to get this information out in the scientific literature,” Penn said. “NEJM asked us to clarify current issues related to the management and understanding of ROP. This forum will allow us to begin to chip away at the old dogma, facilitate a more accurate understanding of ROP and expedite our development of rational treatments leading to better outcomes.”
In the United States, nearly 600 infants each year are blinded from ROP, which develops when abnormal blood vessels grow and spread throughout the retina.
The scarring and bleeding caused by the excess growth can lead to retinal detachment, which is the main cause of visual impairment and blindness in ROP.
Penn holds the Phyllis G. and William B. Snyder Endowed Chair in Ophthalmology and Visual Sciences.
