Scientists at Scripps Research in La Jolla have uncovered a potential new strategy for treating eye diseases that affect millions of people around the world, often resulting in blindness.
Many serious eye diseases — including age-related macular degeneration, diabetic retinopathy and related disorders of the retina — feature abnormal overgrowth of new retinal blood vessel branches, which can lead to progressive loss of vision. It’s a phenomenon called “neovascularization.”
For the past decade and a half, eye doctors have been treating those conditions with drugs that block a protein, VEGF, that’s responsible for spurring new vessel growth. Such drugs have improved the treatment of the conditions but don’t always work well and have potential safety issues.
Scripps Research scientists, in a study published in the Proceedings of the National Academy of Sciences, indicated that a new approach that doesn’t target VEGF directly is highly effective in mice and has broader benefits than a standard VEGF-blocking treatment.
“We were thrilled to see how well this worked in the animal model,” said the study’s co-senior author Rebecca Berlow, a staff scientist in the laboratory of Peter Wright, a professor in the department of integrative structural and computational biology. “There really is a need for another way to treat patients who do not respond well to anti-VEGF treatments.”
“Our findings have important implications for treating these retinal diseases,” said co-senior author Dr. Martin Friedlander, a professor in the department of molecular medicine at Scripps Research, retina specialist and ophthalmologist at Scripps Clinic and president of the Lowy Medical Research Institute.
Dr. Ayumi Usui-Ouchi, a postdoctoral fellow in Friedlander’s laboratory and a visiting assistant professor from the department of ophthalmology at Juntendo University in Tokyo, led the laboratory effort.
Vision-impairing neovascularization in the retina typically represents the body’s faulty attempt to restore a blood supply that has been impaired by aging, diabetes, high blood cholesterol or other factors.
As the small vessels supplying the retina narrow or fail, oxygen levels in the retina decline. This low-oxygen condition, called hypoxia, is sensed by a protein called HIF-1α, which then triggers a complex “hypoxic response.” The response includes boosting production of the VEGF protein to get more blood to areas in need. In principle, this is an adaptive, beneficial response. But chronic hypoxia leads to chronic and harmful — blindness-causing — overgrowth of abnormal, often leaky, new vessels.
Though anti-VEGF drugs stabilize or improve vision quality in most patients, about 40 percent are not significantly helped by the drugs. Moreover, researchers are concerned that the long-term blocking of VEGF, a growth factor needed for the health of many tissues, including the retina, may do harm along with good. Many cases of retinal neovascularization are accompanied by the loss of tiny blood vessels elsewhere in the retina, and blocking VEGF inhibits or prevents their regrowth.
In a 2017 paper in Nature, Berlow and colleagues described the workings of a different protein, CITED2, that naturally dials down the hypoxic response and thus might be the basis for an alternative treatment strategy.
For the new study, the researchers conducted tests in a mouse model of retinal hypoxia and neovascularization, using a fragment of CITED2 that contains its functional, hypoxic-response-blocking elements.
They showed that when a solution of the CITED2 fragment was injected into the eye, it lowered the activity of genes that are normally switched on by HIF-1α in retinal cells and significantly reduced neovascularization. Moreover, it did so while preserving, or allowing to regrow, the healthy capillaries in the retina that would otherwise have been destroyed.
In the same model, the researchers tested a drug called aflibercept, a standard anti-VEGF treatment. It helped reduce neovascularization but did not prevent the destruction of retinal capillaries. However, reducing the dose of aflibercept and combining it with the CITED2 fragment yielded better results than either alone, strongly reducing neovascularization while preserving and restoring retinal capillaries.
CITED2’s ability to combine the two benefits appears to represent a key advance, the study concluded.
The researchers now hope to develop the CITED2-based treatment further, with the ultimate goal of testing it in human clinical trials. ◆
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November 08, 2020 at 02:38AM
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Scripps Research study says new strategy for treating retinal diseases shows promise - La Jolla Light
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