AMD: Gene Expression Pathways React Differently to Various Anti-VEGF Drugs

It was in 1971 that American medical scientist, Judah Folkman, hypothesized that tumor growth was dependent on angiogenesis. Since then, recent research has indicated that anti-vascular endothelial growth factor (VEGF) drugs can increase the size of geographic atrophy in patients with age-related macular degeneration (AMD) and possibly worsen macular. The traditional ways to evaluate the impact drugs have on cells and tissues is to start with cell culture experiments, move on to animal models, and eventually human models. G. Astrid Limb, MSc, PhD, FRCPath, from the Institute of Ophthalmology at the University College London (UCL) has approached these evaluations using the Müller cell line model (MIO-M1).

Baruch Kuppermann, MD, PhD, a professor of ophthalmology and biomedical engineering at the University of California, Irvine, and colleagues looked at gene expression modifications in retinal Müller cells treated with anti-VEGFs. Speaking at the 34^th Annual Scientific Meeting of the American Society of Retina Specialists (ASRS 2016) in San Francisco, California, Kuppermann presented the question — why is there increased atrophy with chronic use of anti-VEGF drugs?

The analysis analyzed four pathways: angiogenesis, antioxidant, inflammation, and apoptosis. The team hypothesized that anti-VEGF drugs can affect non-angiogenesis pathways related to oxidative stress and apoptosis.

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To see if this was the case, they took the Müller cells, plated them, sessile them, and exposed them to 0.5 mg of four drugs — ranibizumab, bevacizumab, aflibercept, and ziv-aflibercept. After 24 hours of exposure, the RNA was isolated and evaluated with reverse transcription.

The anti-VEGF drugs did indeed induce changes in the gene expressions involved in the pathways. As expected, gene expression decreased with all four drugs through the angiogenesis pathway (VEGFA). Kuppermann noted that “interestingly” there was less of a decrease with ziv-aflibercept.

Dubbed by Kuppermann as the most important finding of the study, the analysis revealed that the gene expression levels of antioxidant enzyme (SOD2) decreased with all four anti-VEGF drugs.

Inflammation (IL-18) showed an increase of gene expression. Apoptosis (BCL2L13) had no change with ranibizumab or ziv-aflibercept, but had an increase with bevacizumab.

“The data supports our hypothesis that exposure to anti-VEGF drugs can cause changes in non-angiogenic pathways,” Kupperman said at ASRS 2016. He concluded the presentation by saying that having a better understanding of the impact of these drugs on retinal cells can help progress in treatment options.

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