Bile acid receptor could be innovative target in protecting the vision of premature newborns

It sounds like bile acid in the eye would hurt, but scientists think stimulating one of its receptors can actually help protect the vision of premature newborns.

It's called the farnesoid-X-receptor, or FXR, a bile acid receptor whose expression is significantly diminished in two key cell types affected by retinopathy of prematurity.

Medical College of Georgia scientists have early evidence that targeting that receptor could provide earlier, more impactful treatments for these babies, a process that could be expedited by the fact that the drugs they are studying already are used in people.

Menaka C. Thounaojam, Ph.D., vision scientist focusing on ischemic retinopathies in the MCG Department of Cellular Biology and Anatomy and Culver Vision Discovery Institute at Augusta University, is principal investigator on a new $1.9 million grant (R01 EY034568-01) from the National Eye Institute that is enabling further exploration of that potential.

A small fraction of premature babies develop retinopathy of prematurity, a leading cause of childhood blindness, which at its most severe can lead to formation of leaky blood vessels that further obstruct rather than improve vision and retinal detachment.

Key to normal blood vessel development are astrocytes, normally supportive star-shaped cells that, for example, in the developing eye secrete vascular endothelial growth factor, or VEGF. As the name implies, VEGF is essential to new blood vessel growth, and astrocytes also help lay out the pattern for where endothelial cells, which line blood vessels, need to go and what they should do when they get there.

But in the stressful environment that can come with premature birth, these essential astrocytes may essentially self-destruct, or apoptose, and begin to send the wrong message to endothelial cells.

"Out of all the cell types present in the retina, endothelial cells and astrocytes are the ones specifically expressing this receptor," Thounaojam says of FXR.

It was Thounaojam's lab that found that FXR's expression is reduced in both these key cell types in the face of retinopathy of prematurity.

"Because of that, the pattern, which is supposed to form and guide the endothelial cells to form normal blood vessels, is not able to guide it, which is why endothelial cells will become confused and uncontrolled growth takes place," Thounaojam says.

Based on the data they've already generated, her hypothesis is that better FXR signaling can prevent astrocytes from dying and consequently endothelial cells will get the proper direction for developing functional new blood vessels and babies will have better vision.

She thinks making FXR a target could lead to earlier intervention, rather than current approaches which, for example, try to reduce abnormal blood vessel growth with anti-VEGF treatment or laser therapy to try and stop disease progression.

Treatments today try to address the dysfunctional blood vessel growth that happens in response to perceived hypoxia in the retinas of babies. The hypoxia results as they move from the oxygen supplementation needed to save their lives, to the comparatively low oxygen content in the air we all breathe. The approach they are pursuing should begin to work in the period of hyperoxia that occurs with oxygen supplementation, which is when normal blood vessel development should be happening because the baby should still be developing in the mother. The scientists suspect that that the reduced expression and signaling from FXR that happens in retinopathy of prematurity is key to the destruction that happens instead and likely enhancing its expression will help reduce or eliminate it.

They are looking at two drugs that induce FXR signaling, obeticholic acid, which is already prescribed clinically to treat a liver condition in which the bile ducts are destroyed and works to increase bile production and elimination in the liver, and chendeoxycholic acid, a natural bile acid that also is used clinically to dissolve gallstones. They are looking at the impact of the drugs on different stages of retinopathy of prematurity. They also want to further explore the normal role of FXR in the retina and how that is altered in retinopathy of prematurity using models where FXR has been knocked out of astrocytes and endothelial cells.

Bile acids are primarily made in the liver from cholesterol and released as we eat food to aid digestion and to help with things like cholesterol production and elimination. In addition to those established roles, it's now known that bile acids are made and used in the eye.

Thounaojam was the first to find bile acids in the retina, a finding that both surprised and excited her, and led her to explore what it's doing there normally and in retinopathy of prematurity.

She has laboratory evidence that in the eye, bile acid can be beneficial/protective in retinopathy of prematurity. Positive benefits include protecting the photoreceptor cells, which capture light and turn it into a signal, from degenerating; keeping ganglion cells which reach back to form the optic nerve and to the brain from dying; and cataracts from forming. Others have shown similar benefits in diabetic retinopathy. Similarly, FXR has been shown to be protective of neurons, including reducing inflammation and oxidative stress, which are destructive players in retinopathy of prematurity as well.

While FXR's protective role seems clear in retinopathy of prematurity, its normal role as well as benefits to increasing its expression in this condition need more study, Thounaojam says.

While most premature babies won't have retinopathy of prematurity, at the moment there is no good way to tell who will and won't, Thounaojam notes. Also, some babies can develop problems like cataracts later without early indicators of trouble. Those long-term potential effects of FXR signaling are another angle she is pursuing. She also wants to know any long-term negative impact from the therapies she is pursuing.

"We focus right now on whether the baby has retinopathy of prematurity, whether the baby is blind or not," she says. "But even though the baby Is not blind, they can have other associated vision complications in childhood." So, she is also looking at specifics like visual acuity, leakiness of blood vessels and whether the photoreceptors are working well.

Like their lungs and other organs, a baby's eyes should be fully developed at birth. But some babies born before the usual 40-weeks of gestation, may need oxygen support, such as from a ventilator, then ideally go back to breathing room air as soon as possible, often about the same time they would have been born at term. But the ventilator provides higher oxygen concentrations than the air we breathe so by contrast it can create a sense of too little oxygen, or hypoxia. Blood vessels can begin to grow aggressively and incorrectly, further obstructing rather than supporting vision. Risk factors include things like gestational age and birthweight, how long oxygen supplementation is needed and complications like respiratory distress syndrome.

Retinal development in a mouse, by contrast, finishes up in the days after birth, which enables the scientist to watch how the dynamic of oxygen supplementation followed by room air impacts blood vessel development and what treatments help normalize the development.

Thounaojam notes that potential therapeutics of bile acids have been explored for years. As examples, the bile of black and brown bears being used to removed toxins from the body, stop seizures and improve vision, she says. Bile acids from these bears, for example, have relatively high levels of ursodeoxycholic acid, which is known to have beneficial effects like dissolving gallstones and treating cirrhosis.

Provided by Medical College of Georgia at Augusta University