LA JOLLA, Calif.—Vascular endothelial growth factor (VEGF) has long been a leading target as a potential treatment for eye disease, but now there might be a new approach contending for the top spot. In working with short strands of RNA—or anti-microRNAs—that target and inhibit microRNAs, researchers at The Scripps Research Institute (TSRI) have found a new method for blocking abnormal blood vessel growth, a key factor of vision loss in diseases such as “wet” macular degeneration and diabetic retinopathy.
VEGF is a signal protein that kicks off angiogenesis, the growth of new blood vessels, and is part of a system that helps to correct the situation when blood flow to tissues is inadequate. It is one of the molecules that activates the Ras gene, which must be activated for blood vessel growth to occur. If the body senses low oxygen levels somewhere in the body, it produces VEGF, and blood vessels in the eye begin to grow new vessels when they sense the increased levels of the molecule. In diseases such as “wet” macular degeneration and diabetic retinopathy, abnormal blood vessel growth occurs under or on top of the retina, respectively, leading to eventual vision loss.
Given this chain reaction, researchers have been seeking ways to block VEGF in hopes of cutting this sequence off at the pass; however, according to TSRI’s Prof. Martin Friedlander, M.D, Ph.D., senior author of the study, inhibiting VEGF comes with its own problems.
“VEGF does more than just regulate blood vessel growth, it performs a very important trophic function; it’s very important for survival of neurons and blood vessels,” Friedlander explains. “So if you completely block VEGF, there’s a good chance you’re going to observe what we call off-target effects, that is the effects that aren’t related to its anti-angiogenic activity. There’s a published paper showing at least in animal models—we don’t know if it’s entirely clear in people, but we suspect this may be true also—that indeed if you completely shut down VEGF under certain circumstances, you will see death of neurons and blood vessels.
“The second thing is that whenever you knock down one pathway by which the body can make new blood vessels, you’ll get a compensatory upregulation of other pathways,” he continues. “And again, we know this is shown in animal models that if you knock down VEGF, you see increases in other molecules which are capable of making new blood vessels. So what one would like to do is either use lower doses of these [anti-VEGF] drugs so you avoid some of these off-target effects, or better yet, interfere with these angiogenic pathways downstream from these effects that you’re trying to avoid.”
Friedlander and his colleagues published a paper last year in the Journal of Clinical Investigation in which they demonstrated that VEGF is key to healthy vision, and complete inhibition can kill the light-sensing cells in the eyes, exacerbating the issue of vision loss.
“Our collaborator, David Cheresh, and his lab observed that microRNAs could be used to target neovascularization at a point in the pathway ‘downstream’ of VEGF,” said Peter Westenskow, Ph.D., a postdoctoral fellow at TSRI and first author of the study. “We have now shown that microRNAs can inhibit the actions of multiple pro-angiogenic compounds including, but not limited to, VEGF. Blocking these ‘downstream’ targets would stop the aberrant blood vessel sprouting while maintaining the health of the normal blood vessels in the eye.”
So Friedlander and his colleagues set about trying to tackle this new approach, and found that the microRNA treatments were capable of blocking abnormal vessel growth—without causing damage to existing vasculature or neurons—in three separate models of neovascular eye disease.
Their work focused on microRNA-132, which plays a role in mediating angiogenesis. The team blocked microRNA-132 in the eye and prevented activation of Ras by targeting the microRNA with a small 22-base anti-microRNA, results they saw in all three models. Friedlander says that compared to the VEGF inhibitors, “We do indeed in our animal models, under the control conditions, see as good if not better inhibition using the anti-microRNA, the microRNA targeting, as we do with using one of the commercially available VEGF antagonists.” As an added benefit, he points out, they don’t see the compensatory upregulation of other angiogenic molecules in response, as is the case when VEGF is inhibited.
“We believe that targeting and inhibiting the action of microRNAs involved could represent a novel and effective way to treat a broad range of neovascular eye diseases such as diabetic retinopathy, macular degeneration and macular telangiectasia,” said Friedlander. “We are excited about this approach to halting abnormal blood vessel growth without inducing off-target side effects.”
Moving forward, he says they’d like to advance their approach toward clinical trials, and notes that several potential partners have expressed interest in their work.
The study, “Ras pathway inhibition prevents neovascularization by repressing endothelial cell sprouting,” appeared in the Journal of Clinical Investigation. This work was funded by a five-year, $10.2-million grant awarded in 2012 from the National Eye Institute of the National Institutes of Health.
