Scientists believe that stimulating one of the bile acid receptors may help protect vision in premature newborns. It’s called farnesoid-X-receptor, or FXR, a bile acid receptor whose expression is significantly decreased in two key cell types affected by retinopathy of prematurity.
Scientists at the Medical College of Georgia have preliminary evidence that targeting that receptor could provide earlier, more impactful treatments for these babies, a process that could be accelerated by the fact that the drugs they are studying are already used in people.
Menaka C. Thounaojam, PhD, a vision scientist focusing on ischemic retinopathies in the Department of Cell Biology and Anatomy at MCG and the Culver Vision Discovery Institute at Augusta University, is the principal investigator on a new $1.9 grant million (R01 EY034568-01) from the National Eye Institute that is allowing further exploration of that potential.
A small fraction of premature babies develop retinopathy of prematurity , a leading cause of childhood blindness, which in its most severe form can lead to the formation of leaky blood vessels that further obstruct rather than improve vision and retinal detachment. .
The key to normal blood vessel development is astrocytes , typically star-shaped supporting cells that, for example, in the developing eye secrete vascular endothelial growth factor or VEGF. As its name implies, VEGF is essential for the growth of new blood vessels, and astrocytes also help blueprint where endothelial cells, which line blood vessels, should go and what they should do when they get there.
But in the stressful environment that can arise with premature birth, these essential astrocytes can essentially self-destruct, or undergo apoptosis, and begin sending the wrong message to endothelial cells. “Of all the cell types present in the retina, endothelial cells and astrocytes are the ones that specifically express this receptor,” Thounaojam says of FXR.
It was Thounaojam’s laboratory that discovered that FXR expression is reduced in these two key cell types in retinopathy of prematurity. “So the pattern, which is supposed to form and guide the endothelial cells to form normal blood vessels, cannot guide it, so the endothelial cells will get confused and uncontrolled growth will occur,” says Thounaojam.
Based on the data they’ve already generated, their hypothesis is that better FXR signaling can prevent astrocytes from dying, and consequently, endothelial cells will get proper direction to grow new functional blood vessels and babies will have better vision. She thinks making FXR a target could lead to earlier intervention, rather than current approaches that, for example, try to reduce abnormal blood vessel growth with anti-VEGF treatment or laser therapy to try to stop the progression. of the illness.
Current treatments attempt to address the dysfunctional blood vessel growth that occurs in response to perceived hypoxia in infants’ retinas.
Hypoxia occurs when they go from the supplemental oxygen needed to save their lives to the comparatively low oxygen content in the air we all breathe . The approach they pursue should begin to work in the period of hyperoxia that occurs with oxygen supplementation, which is when normal blood vessel development should be occurring because the baby should still be developing in the mother. Scientists suspect that the reduced expression and signaling of FXR that occurs in retinopathy of prematurity is key to the destruction that occurs instead, and improving its expression will likely 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 bile ducts are destroyed and works to increase the production and elimination of bile in the liver, and bile acid. deoxycholic, a natural bile acid that is also used clinically to dissolve gallstones. They are looking at the impact of medications on different stages of retinopathy of prematurity. They also want to further explore the normal role of FXR in the retina and how it is altered in retinopathy of prematurity using models in which FXR has been removed from astrocytes and endothelial cells.
Bile acids are primarily produced in the liver from cholesterol and are released as we eat food to aid digestion and help with things like the production and elimination of cholesterol. In addition to those established functions, bile acids are now known to be made and used in the eye.
Thounaojam was the first to find bile acids in the retina, a finding that surprised and excited her, and led her to explore what it does there normally and in retinopathy of prematurity.
You have laboratory evidence that, in the eye, bile acids may be beneficial/protective in retinopathy of prematurity. Positive benefits include protecting photoreceptor cells, which capture light and convert it into a signal, from degeneration; prevent the ganglion cells that regress to form the optic nerve and brain from dying; and cataracts from forming. Others have shown similar benefits in diabetic retinopathy. Similarly, FXR has been shown to protect neurons, including reducing inflammation and oxidative stress, which are also destructive factors in retinopathy of prematurity.
While the protective role of FXR seems clear in retinopathy of prematurity, its normal role, as well as the benefits of increasing its expression in this condition, need further study, says Thounaojam.
While most premature babies won’t have retinopathy of prematurity, there’s currently no good way to know who will and won’t, Thounaojam says. Additionally, some babies may develop problems such as cataracts later without early indicators of problems. Those potential long-term effects of FXR signaling are another angle he’s pursuing. She also wants to know any long-term negative impacts of the therapies she is following.
“Right now we focus on whether the baby has retinopathy of prematurity, whether the baby is blind or not,” she says. “But even if the baby is not blind, she may have other associated visual complications in childhood.” Therefore, she is also looking at details such as visual acuity, blood vessel leakage, and whether photoreceptors are working well.
Like his lungs and other organs, a baby’s eyes must be fully developed at birth. But some babies born before the usual 40 weeks of gestation may need oxygen support, such as a ventilator, and then, ideally, return to breathing room air as soon as possible, often around the same time they would have been born at term. But the ventilator provides higher concentrations of oxygen than the air we breathe, so it can instead create a feeling of oxygen deprivation or hypoxia. Blood vessels may begin to grow aggressively and incorrectly, further obstructing vision rather than supporting it. Risk factors include things like gestational age and birth weight, how long oxygen supplementation is needed, and complications like respiratory distress syndrome.
Retinal development in a mouse, by contrast, ends in the days after birth, allowing the scientist to observe how the dynamics of oxygen supplementation followed by ambient air affects blood vessel development and what treatments They help normalize development.
Thounaojam notes that potential bile acid therapies have been explored for years. As examples, bile from black and brown bears is used to remove toxins from the body, stop seizures and improve vision, she says. The bile acids from these bears, for example, have relatively high levels of ursodeoxycholic acid, which is known to have beneficial effects such as dissolving gallstones and treating cirrhosis.
