Scientists from the Medical College of Georgia have discovered a drug that, in combination with a new target, appears to stop vision loss in premature babies. In preterm births, a still-immature retina can develop retinopathy of prematurity, a potentially severe eye disorder. The development of blood vessels of the retina is usually complete by the time of birth; however, in the case of premature births, the blood vessels remain unable to cultivate properly. As premature babies are put in the incubator, it creates a feeling that their still-developing retina is getting an excessive amount of oxygen, which can restrict normal blood vessel development. This leads to the feeling of relative hypoxia and insufficient oxygen reaching the retina, which can prompt the formation of dysfunctional blood vessels in the eye and lead to poor vision, among other issues.
The researchers used an animal model of retinopathy of prematurity to show that the small molecule K604, which was initially being looked into for Alzheimer’s and cancer, can stop the development of leaky, obstructive blood vessels in the retina. In addition, it reduces inflammation and enables the development of more normal blood vessels, leading to better vision for the babies. K604 works by blocking ACAT1, an enzyme that converts free cholesterol and long-chain fatty acids to cholesterol esters, allowing them to be more easily removed by the liver. In premature babies, the low levels of oxygen in the retina may stimulate the formation of dysfunctional blood vessels in the eye and lead to an accumulation of lipids, fats, and these cholesterol esters. Inhibiting ACAT1 helps restore normal metabolism to a situation that has gone wrong.
During hypoxia, cholesterol levels in the blood and the retina increase, and scientists believe that swollen microglial cells and resident macrophages lead to more ACAT1 and cholesterol esters. Cholesterol esters promote inflammation, resulting in the increased activity of TREM1, which helps turn up short-term inflammation in response to a virus. When ACAT1 is removed, a destructive cascade is eliminated, reducing inflammation and growth of abnormal blood vessels. The scientists suggest that inhibiting ACAT1 makes microglia/macrophages less inflammatory and do more angiogenic repair. Removing cholesterol from the equation also stops the destructive cascade.
ACAT1 expression and activity in active microglia have been implicated in several health issues such as Alzheimer’s, cancer, and atherosclerosis. K604 was initially developed to work against excessive cholesterol in atherosclerosis, but it was not effective in treating the condition. Cholesterol ester levels are not currently measured clinically like levels of LDL and HDL cholesterol. A clinical trial on K604 in babies should be the next step to test the new discovery that dissolves obstructive blood vessels and enables normal ones.
