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Discovery & Development Drug Discovery, Formulation

Recycling for ROP

Scientists at the Medical College of Georgia, USA, have discovered a new use for an existing drug that could halt the development of retinopathy of prematurity (ROP), a potentially blinding eye disorder affecting premature newborns (1). The disorder occurs when premature babies – whose retinas are not yet fully developed – transition from low-level oxygen environs of the womb to much higher levels of an incubator. This sensation inhibits normal blood vessel development of the retina, which leads to hypoxia and the accumulation of lipids and fats in the eye.

Using an animal model of ROP, researchers found that the small molecule K604 – a drug originally developed to combat excessive cholesterol in atherosclerosis – can block the development of obstructive blood vessels in the retina, reduce inflammation, and enable normal blood vessel growth. K604, which is also used for Alzheimer’s and cancer treatment, does this by blocking acyl-Coenzyme A: cholesterol acyl transferase 1 (ACAT1), an enzyme that allows toxic cholesterol to build up in the retina of premature babies, inducing inflammation and retinal injury when left untreated. By inhibiting ACAT1 (acyl-Coenzyme A: cholesterol acyl transferase 1), K604 is able to help restore normal metabolism to the retina and prevent pathological neovascularization. 

The scientists believe that ACAT1 inhibition through K604, which has already been proven to be safe in adults and have no effect on VEGF levels, might help restore the retina to a normal metabolism and prevent pathological neovascularization. However, they suggest further steps must be taken to translate their findings for clinical evaluation of the drug in babies. They also aim to explore the use of K604 for treating diabetic retinopathy, which occurs in around one-third of patients with diabetes. 

Researchers concluded, “we have identified a novel mechanism of Retinal Neovascularization (RNV) that involves a link between the cholesterol pathway ( low-density lipoprotein receptor, ACAT1, Cholesteryl ester) and activation of the inflammatory mediators TREM1 and MCSF. Hypoxia increases LDL cholesterol uptake into retinal cells, leading to activation of ACAT1. This, in turn, causes the accumulation of toxic levels of CE in retinas and promotes retinal inflammation characterized by upregulation of TREM1, MCSF, and inflammatory cytokines. Systemic inhibition of ACAT1 could represent a new target to treat pathological RNV in ischemic retinopathies without altering levels of VEGF and avoiding the side effects of intravitreal injections.”

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  1. SAH Zaidi et al., J Neuroinflammation 20, 14 (2023). PMID: 36691048.
About the Authors
Jamie Irvine

Associate Editor, The Medicine Maker

Alun Evans

Associate Editor

Coming from a creative writing background, I have a great interest in fusing original, narrative-driven concepts with informative, educational content. Working at The Ophthalmologist allows me to connect with the great minds working in the field of contemporary eye care, and explore the human element involved in their scientific breakthroughs.

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