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29/Oct/2020

New strategy for treating common retinal diseases shows promise

A potential treatment based on a natural protein may offer broader benefits than existing drugs

Scientists at Scripps Research 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 these conditions with drugs that block a protein, VEGF, that’s responsible for spurring new vessel growth. Such drugs have improved the treatment of these conditions, but don’t always work well and have potential safety issues. The Scripps Research scientists, in a study published in the Proceedings of the National Academy of Sciences, showed 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,” says Rebecca Berlow, PhD, co-senior author of the study. “There really is a need for another way to treat patients who do not respond well to anti-VEGF treatments.”

Berlow is a staff scientist in the laboratory of Peter Wright, PhD, professor and Cecil H. and Ida M. Green Investigator in the Department of Integrative Structural and Computational Biology. The co-senior author on the study was Martin Friedlander, MD, PhD, professor in the Department of Molecular Medicine at Scripps Research, retina specialist and ophthalmologist in the Division of Ophthalmology at Scripps Clinic and President of the Lowy Medical Research Institute.

Ayumi Usui-Ouchi, MD, PhD, a post-doctoral fellow in Friedlander’s laboratory and visiting assistant professor from the Department of Ophthalmology at Juntendo University in Tokyo, Japan, led the laboratory effort.

“Our findings have important implications for treating these retinal diseases,” Friedlander says.

New alternative to an imperfect solution

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-1?, which then triggers a complex “hypoxic response.” This response includes boosting production of the VEGF protein to bring 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.

Although anti-VEGF drugs stabilize or improve vision quality in most patients, about 40 percent are not significantly helped by these 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 the re-growth of these vessels.

In a 2017 paper in Nature, Berlow and colleagues described the workings of a different protein that naturally dials down the hypoxic response and thus might be the basis for an alternative treatment strategy. The protein, CITED2, is produced by HIF-1? as part of the hypoxic response, and apparently functions as a “negative feedback” regulator that blocks HIF-1?’s ability to switch on hypoxic response genes — keeping the response from becoming too strong or staying on too long.

A winning combination

For the new study, the team of 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-1? in retinal cells, and significantly reduced neovascularization. Moreover, it did so while preserving, or allowing to re-grow, the healthy capillaries in the retina that would otherwise have been destroyed — researchers call it “vaso-obliteration” — in this model of retinal disease.

In the same mouse 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 these two benefits appears to represent a key advance, the researchers conclude.

“Most hypoxia-related retinal disorders, such as diabetic retinopathy, have extensive capillary loss in late stages of disease, leading to neuronal cell death and vision loss,” Friedlander says. “No current treatment has any therapeutic benefit for this aspect of the disorder.”

The researchers now hope to develop the CITED2-based treatment further, with the ultimate goal of testing it in human clinical trials.

 

Materials provided by Scripps Research InstituteNote: Content may be edited for style and length.


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24/Jun/2019

Eyes hold clues for treating severe autism more effectively

Vocabulary tests for individuals with the severest forms of autism spectrum disorder, or ASD, are notoriously inaccurate. They commonly ask the test-taker to point to an illustration after hearing a spoken word, measuring the ability to understand and perform a task as much as word knowledge.

The implications are significant. Poor assessments result not only in teaching strategies that are ineffective but also make researchers wary, leading to a shortage of research on individuals with Level 3 ASD, the diagnosis given to the most severe forms of autism, that could help improve their quality of life.

That’s according to Emily Coderre, lead author of a new study in the journal Cognitive and Behavioral Neurology and a faculty member in the University of Vermont’s Department of Communication Science and Disorders.

In the new study, Coderre and colleagues at Johns Hopkins Medicine demonstrate that assessment tools capturing implicit signs of word knowledge like eye movement among those with Level 3 ASD — tools that have rarely been used with this group — offer the potential to be more accurate than traditional behavioral assessments, closely matching the reports of parents and caregivers, the current “gold standard” for determining an individual’s vocabulary knowledge.

“Children and adults with severe ASD often score much lower than they should on traditional language assessments,” Coderre said. “They may not understand the instructions or be unable to point to a picture after hearing the spoken word. Or they may be frightened by the equipment or simply not care to participate. The new study points the way toward a much better approach.”

Three implicit measures of word knowledge

To assess vocabulary knowledge among five adults with Level 3 ASD, researchers in the study used what are called implicit measures of word knowledge.

In one test researchers used a technique called eye movement monitoring. After hearing a spoken word, which matched one of four illustrations on a computer screen, the researchers tracked the subjects’ eye movements. If their eyes quickly chose the matching visual and stayed with it, that signaled knowledge of the word. If the eyes flitted from one object to the next, it demonstrated the word was probably not known.

In a second test called pupillary dilation, subjects again heard a spoken word and were shown four visuals. If the pupils dilated, that signaled cognitive effort, and the probability that the word was not known. If pupils did not dilate, that likely demonstrated knowledge of the word.

In a third test, researchers used electroencephalography to measure brain activity in the research subjects. Subjects heard a word and were shown an image that either matched or did not match it. Earlier research has shown there are typical brain patterns for congruent and incongruent pairs of words and images, enabling the researchers to infer whether the word was known based on these electrical signatures.

The three measures had varying degrees of accuracy with each of the five research subjects. Although the researchers concluded that these implicit measures show promise in providing estimates of vocabulary knowledge, this variability suggests that these assessments should be tailored to each individual.

An earlier study by the research team offered further validation of the research findings. That study found that the three implicit measures were highly accurate in assessing word knowledge among a group of adults who did not have ASD.

Better interventions, more knowledge

Given the small research sample, the research findings are preliminary. But their potential implications are significant, Coderre said.

Implicit measures of vocabulary could result in more effective interventions that are tailored to the true language knowledge of the individual.

“Language is often one of the areas where individuals with autism struggle, especially at the more severe end of the spectrum, where a large percentage have little to no functional language,” Coderre said. “Anything we can do to improve their language outcomes will improve their quality of life.”

The new tools could also result in more research into those with severe ASD, she said, not only in language acquisition but in other areas of cognition.

Nonverbal intelligence testing often relies on visual clues, for instance, she said. Subjects might be shown an image of a puzzle with a missing piece and be asked to find the piece among several options, a task well suited to the EM and PD testing.

“These techniques could very well be extended to other domains,” Coderre said.

That could help address a challenge in the field — the huge lack of literature on individuals with Level 3 ASD.

“There’s so much focus on the milder end of the spectrum, the people who are more functionally verbal, that people on the more severe end of the spectrum tend to be overlooked,” Coderre said.

“With measures like these, we can do not only more interventions-based research, but also work with this population in general, so we can better understand how their strengths and weaknesses are similar to or different from other individuals on the spectrum. The more understanding we have, the more help we can offer.”


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