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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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New insight on how people with retinal degenerative disease can maintain their night vision for a relatively long period of time has been published today in the open-access eLife journal.

The study suggests that second-order neurons in the retina, which relay visual signals to the retinal ganglion cells that project into the brain, maintain their activity in response to photoreceptor degeneration to resist visual decline — a process known as homeostatic plasticity. Rod photoreceptors are the cells responsible for the most sensitive aspects of our vision, allowing us to see at night, but can be lost during retinal degenerative disease.

The new findings pave the way for further research to understand how our eyes and other sensory systems respond and adapt to potentially compromising changes throughout life.

“Neuronal plasticity of the inner retina has previously been seen to occur in response to photoreceptor degeneration, but this process has been mostly considered maladaptive rather than homeostatic in nature,” explains co-first author Henri Leinonen, a postdoctoral researcher at the University of California, Irvine, US. “Our study was conducted at a relatively early stage of disease progression, while most previous studies focused on severe disease stages, which may account for the discrepancy. Very recently, several studies using triggered photoreceptor loss models have shown adaptive responses in bipolar cells — cells that connect the outer and inner retina. But whether such adaptation occurs during progressive photoreceptor degenerative disease, and whether it helps to maintain visual behavior, was unknown.”

To address this question, Leinonen and colleagues studied a mouse model of retinitis pigmentosa. This is the name given to a group of related genetic disorders caused by the P23H mutation in rhodopsin, a protein that enables us to see in low-light conditions. Retinitis pigmentosa causes the breakdown and loss of rod-shaped photoreceptor cells in the retina, leading to difficulties seeing at night.

The team combined whole-retinal RNA-sequencing, electrophysiology and behavioral experiments in both healthy mice and those with retinitis pigmentosa as the disease progressed. Their experiments showed that the degeneration of rod photoreceptors triggers genomic changes that involve robust compensatory molecular changes in the retina and increases in electrical signalling between rod photoreceptors and rod bipolar cells. These changes were associated with well-maintained behavioural night vision despite the loss of over half of the rod photoreceptor cells in mice with retinitis pigmentosa.

“This mechanism may explain why patients with inherited retinal diseases can maintain their normal vision until the disease reaches a relatively advanced state,” says co-first author Nguyen Pham, Graduate Research Assistant at the John A. Moran Eye Center, University of Utah Health, Salt Lake City, US. “It could also inspire novel treatment strategies for diseases that lead to blindness.”

“Our results suggest retinal adaptation as the driver of persistent visual function during photoreceptor degenerative disease,” concludes senior author Frans Vinberg, PhD, Assistant Professor at the John A. Moran Eye Center, University of Utah Health. “Additional research is now needed to discover the exact homeostatic plasticity mechanisms that promote cellular signalling and visual function. This could help inform the development of potential new interventions to enhance homeostatic plasticity when needed.”


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When the eye isn’t getting enough oxygen in the face of common conditions like premature birth or diabetes, it sets in motion a state of frenzied energy production that can ultimately result in blindness, and now scientists have identified new points where they may be able to calm the frenzy and instead enable recovery.

In this high-energy environ, both the endothelial cells that will form new blood vessels in the retina — which could improve oxygen levels — and nearby microglia — a type of macrophage that typically keeps watch over the retina — prefer glycolysis as a means to turn glucose into their fuel.

Medical College of Georgia scientists have shown that in retinal disease, the excessive byproducts of this inefficient fuel production system initiate a crescendo of crosstalk between these two cell types. The talk promotes excessive inflammation and development of the classic mass of leaky, dysfunctional capillaries that can obstruct vision and lead to retinal detachment, says Dr. Yuqing Huo, director of the Vascular Inflammation Program at MCG’s Vascular Biology Center.

The major byproduct of glycolysis is lactate, which also can be used as a fuel, for example, by our muscles in a strenuous workout. Microglia also need some lactate from the endothelial cells. But in disease, the lactate is in definite oversupply, which instead supports this destructive conversation between cells, says Huo, corresponding author of the study in the journal Science Translational Medicine.

“This is a major problem in our country, loss of vision because of compromised oxygen for a variety of reasons,” says Dr. Zhiping Liu, postdoctoral fellow in Huo’s lab and the study’s first author. “We hope this additional insight into how that process destroys vision, will enable us to find better ways to intervene,” Liu says.

In a low-oxygen environ, endothelial cells produce not only a lot of lactate, but also factors that encourage nearby microglia to be more active, and to use glycolysis to get more active, Huo says.

In reality, microglia don’t need the encouragement because they already also seem to prefer this method of energy production. But the extra lactate sent their way does spur them to produce even more energy and consequently even more lactate, Huo says.

The normally supportive immune cells also start overproducing inflammation-promoting factors like cytokines and growth factors that promote blood vessel growth or angiogenesis, which, in a vicious loop, further turns up glycolysis by the endothelial cells, which are now inclined to proliferate excessively.

“The reciprocal interaction between macrophages and (endothelial cells) promotes a feed-forward relationship that strongly augments angiogenesis,” they write.

The destructive bottom line is termed pathological angiogenesis, a major cause of irreversible blindness in people of all ages, the scientists say, with problems like diabetic retinopathy, retinopathy of prematurity and age-related macular degeneration.

“Our eyes clearly do not have sufficient oxygen, and they end up trying to generate more blood vessels through this process called pathological angiogenesis, which is really hard to control,” Huo says.

The excessive sprouting and proliferation of endothelial cells is central to the destruction, and glycolysis is central to their sprouting and proliferation but the exact mechanisms that trigger all the glycolysis and crosstalk between endothelial cells and microglia have been unknown, they write.

“In all these conditions, there is something wrong with the tissue that causes the blood vessels to not behave properly,” says co-author Dr. Ruth B. Caldwell, cell biologist in the Vascular Biology Center. “It’s a bad state,” she says, which they want to help normalize.

As they are finding more about how the conversation goes bad between these two cells, they are seeing new logical points to do that. When they knock out the most potent activator of glycolysis, called Pfkfb3, from the microglia, lactate production clearly goes down and the cells no longer aid production of dysfunctional capillaries. Conversely, expression of both the messenger RNA that enables production of Pfkfb3 and lactate are significantly higher in the cells when oxygen levels are low.

Agents that stop these cells’ over-the-top use of glycolysis could be good therapeutic approaches, they say. Blocking excessive lactate production could be another. Stopping the microglia from lapping up too much lactate also significantly suppresses pathological angiogenesis in their lab studies. Agents that normalize endothelial cell growth might work as well.

While genetic manipulation was used for much of their lab work to date, the scientists are now looking at chemicals that might work at these various points. A problem is that many drugs that suppress glycolysis have numerous unwanted effects, so they are working to more selectively intervene. They note that since the use of glycolysis by macrophages is critical to support of a healthy immune response, localized inhibition should yield the desired response without affecting the immune response.

Current treatments for abnormal blood vessel development and related leaking and swelling include suppressing vascular endothelial growth factor, or anti-VEGF, which, as the name implies, is a key factor in endothelial cell growth, may require ongoing injections in the eye and gets decent results in conditions like diabetic retinopathy. But anti-VEGF therapy really does not facilitate repair, says Caldwell. The scientists have early evidence their intervention strategies may, because they intervene earlier and help normalize the “bad” environment. “We get repair and restoration,” Caldwell says.

Huo and his colleagues are among those who have shown that glycolysis is critical to the sprouting of endothelial cells and that mice lacking Pfkfb3 have impaired angiogenesis.

Endothelial cells, which line all our blood vessels, are one of the first things laid down when we make new blood vessels. In the retina, they start making tiny tunnels that ideally will become well-functioning capillaries, blood vessels so small that a single red blood cell may have to fold up just to get through. These thin-skinned blood vessels are the point where oxygen, fluid and nutrients are provided to body tissue, then blood gets routed back through the venous system to the heart where the process starts anew.

Endothelial cells grow accustomed to glycolysis when they are helping make our bodies in the early, no-oxygen days during development, Huo says.

The usual job of microglia includes keeping an eye out for invaders, like a virus, and keeping connections between nerves, called synapses, trimmed up.

Caldwell and Huo also are faculty members in the James and Jean Culver Vision Discovery Institute at Augusta University and the MCG Department of Cellular Biology and Anatomy.

The research was supported by the American Heart Association and the National Institutes of Health.


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In studies with lab-grown human cells and in mice, Johns Hopkins Medicine researchers have found that an experimental drug may be twice as good at fighting vision loss as previously thought.

In studies with lab-grown human cells and in mice, Johns Hopkins Medicine researchers have found that an experimental drug may be twice as good at fighting vision loss as previously thought.

The new research shows that the compound, named AXT107, stops abnormal blood vessels in the eye from leaking vision-blocking fluids. These results build on previous research that showed the same compound stopped the growth of abnormal vessels in animal studies of the blinding disease diabetic macular edema and wet age-related macular degeneration.

Diabetic macular edema and wet age-related macular degeneration are the leading causes of vision loss in the U.S. Approximately 750,000 Americans age 40 and older have diabetic macular edema, and wet age-related macular degeneration affects over 1.6 million Americans age 50 and older. Both diseases can eventually cause blindness if untreated.

Current drugs for diabetic macular edema and wet age-related macular degeneration focus on halting the growth of these abnormal vessels to preserve what vision is left. The current standard of treatment is monthly injections directly into the eye to suppress new blood vessel growth. These frequent visits can be a burden for patients due to the discomfort, a small risk for each injection and, for some patients, difficulty getting to the appointment because their vision is not good enough to drive.

“Our findings give us a better understanding of how this potential treatment stops the disease from progressing and does it more quickly, efficiently, and has a longer duration than current drugs used in people with vision loss of this kind,” says Aleksander Popel, Ph.D., professor of biomedical engineering at the Johns Hopkins University School of Medicine.

The study was published in the Feb. 21 issue of the Journal of Clinical Investigation Insight.

In healthy eyes, the cells that make up blood vessels are bound together by proteins residing on the surface of the cell that are directed into place by Tie 2, another protein. Tie2 proteins pack tightly together where cells meet their neighbors and act like Velcro to create a fluid-tight connection between cells in the blood vessel’s wall. In diabetic macular edema, the Tie2 proteins disperse across the cell and no longer can maintain the fluid-tight barrier between the inside of a blood vessel and the outside. Gaps form between the cells, allowing fluids to permeate into the surrounding tissue.

To understand how the drug they developed could strengthen these connections, the researchers designed a series of experiments to explore how AXT107 affects the control of Tie2 and the Velcro-like proteins.

In their first experiment, the researchers used cells derived from human blood vessels grown in the lab that mimicked those seen in wet age-related macular degeneration. When they added the AXT107 drug to these cells, the researchers found that AXT107 initiated a series of changes to cellular proteins. Using a technique to measure protein changes, the researchers found that Tie2 proteins seemed to migrate across the cell. Groups of Tie2 proteins began to congregate where cells met their neighbors, and began rebuilding connections with other blood vessel cells.

The researchers note that when observed under a microscope, the cells went from jagged-looking around the edges to having smooth and continuous outer edges that could be better suited for one cell to fit snugly against another. “It was like zipping them up with a zipper,” says Popel.

The researchers further tested whether these smooth cells could create a watertight barrier, which would be necessary to create a blood vessel that doesn’t leak. So they grew the cells in a single layer and tested whether fluid could pass through by pouring a fluorescent liquid on top of the cells and checking to see if any of the glowing liquid ended up underneath. The researchers observed that cells treated with 100 ?M of the AXT107 drug allowed 2.5 times less dye through the cell layer than control cells receiving no drug. This showed the researchers that the drug helped blood vessel cells create a watertight seal between them.

The researchers next wanted to see if the same effect could be achieved in living blood vessels. They used a fluorescent dye to observe the blood vessels in the eyes of normal mice and mice genetically engineered to mimic human macular degeneration. In the healthy mice, the researchers observed glowing blood vessels with crisp edges and very little fluorescence outside of the vessel. However, in the mice with macular degeneration, glowing liquids passed through the blood vessels, blurring the barrier between blood vessels and the surrounding tissues.

The researchers treated the engineered mice with leaky blood vessels, like those seen in macular degeneration, with injections of the AXT107 peptide into the animals’ eyes. After four days, the researchers found that in mice treated with AXT107, about half as much of the fluorescent dye leaked from their vessels as in animals that received saline injections containing no drug. These results, say researchers, show that the AXT107 drug was able to seal up leaking vessels and prevent vision-blocking fluids from permeating into the surrounding tissue.

Popel says previous studies of AXT107 in animal models showed the drug lasted longer than current treatments by forming a small clear gel of slow-releasing drug in the eye. If proved effective in humans, patients might need only one or two injections to the eye per year, instead of the monthly injections that are the current standard of care.

Popel says AXT107 provides a new therapeutic approach that targets two clinically validated pathways for retina diseases while the anti-VEGF agents only target one aspect of the disease. “In addition to potentially improving the response for patients, the longer duration of AXT107 may allow for less frequent dosing, thus reducing the treatment burden for patients,” says Popel.

The researchers say they plan to test the AXT107 peptide for safety and efficacy in clinical trials of people with diabetic macular edema next year.

Story Source:

Materials provided by Johns Hopkins Medicine. Note: Content may be edited for style and length.


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New Treatment could improve and prolong sight in those suffering vision loss

Millions of Americans are progressively losing their sight as cells in their eyes deteriorate, but a new therapy developed by researchers at the University of California, Berkeley, could help prolong useful vision and delay total blindness.

The treatment — involving either a drug or gene therapy — works by reducing the noise generated by nerve cells in the eye, which can interfere with vision much the way tinnitus interferes with hearing. UC Berkeley neurobiologists have already shown that this approach improves vision in mice with a genetic condition, retinitis pigmentosa, that slowly leaves them blind.

Reducing this noise should bring images more sharply into view for people with retinitis pigmentosa and other types of retinal degeneration, including the most common form, age-related macular degeneration.

“This isn’t a cure for these diseases, but a treatment that may help people see better. This won’t put back the photoreceptors that have died, but maybe give people an extra few years of useful vision with the ones that are left,” said neuroscientist Richard Kramer, a professor of molecular and cell biology at UC Berkeley. “It makes the retina work as well as it possibly can, given what it has to work with. You would maybe make low vision not quite so low.”

Kramer’s lab is testing drug candidates that already exist, he said, though no one suspected that these drugs might improve low vision. He anticipates that the new discovery will send drug developers back to the shelf to retest these drugs, which interfere with cell receptors for retinoic acid. Many such drug candidates were created by pharmaceutical companies in the failed hope that they would slow the development of cancer.

“There has been a lot of excitement about emerging technologies that address blinding diseases at the end stage, after all of the photoreceptors are lost, but the number of people who are candidates for such heroic measures is relatively small,” Kramer said. “There are many more people with impaired vision — people who have lost most, but not all, of their photoreceptors. They can’t drive anymore, perhaps they can’t read or recognize faces, all they have left is a blurry perception of the world. Our experiments introduce a new strategy for improving vision in these people.”

Kramer and his UC Berkeley colleagues reported their results this week in the journal Neuron.

‘Ringing in the eyes’

WordResearchers have known for years that the retinal ganglion cells, the cells that connect directly with the vision center in the brain, generate lots of static as the light-sensitive cells — the photoreceptors — begin to die. This happens in inherited diseases such as retinitis pigmentosa, which afflicts about one in 4,000 people worldwide, but it may also occur in the much larger group of older people with age-related macular degeneration, a disease that affects the crucial part of the retina needed for precise vision. The sharp edges of an image are drowned in such static, and the brain is unable to interpret what’s seen.

Kramer focused on the role of retinoic acid after he heard that it was linked to other eye changes resulting from retinal degeneration. The dying photoreceptors — the rods, sensitive to dim light, and the cones, needed for color vision — are packed with proteins called opsins. Each opsin combines with a molecule of retinaldehyde, to form a light-sensitive protein called rhodopsin.

“There are 100 million rods in the human retina, and each rod has 100 million of these sensors, each one sequestering retinaldehyde,” he said. “When you start losing all those rods, all that retinaldehyde is now freely available to get turned into other things, including retinoic acid.”

Kramer and his team found that retinoid acid — well-known as a signal for growth and development of embryos — floods the retina, stimulating the retinal ganglion cells to make more retinoic acid receptors. It’s these receptors that make ganglion cells hyperactive, creating a constant buzz of activity that submerges the visual scene and prevents the brain from picking out the signal from noise.

“When we inhibit the receptor for retinoic acid, we reverse the process and shut off the hyperactivity. People who are losing their hearing often get tinnitus, or ringing in the ears, which only makes matters worse. Our findings suggest that retinoic acid is doing something similar in retinal degeneration — essentially causing ‘ringing in the eyes,'” Kramer said. “By inhibiting the retinoic acid receptor, we can decrease the noise and unmask the signal.”

The researchers sought out drugs known to block the receptor and showed that treated mice could see better, behaving much like mice with normal vision. They also tried gene therapy, inserting into ganglion cells a gene for a defective retinoic acid receptor. When expressed, the defective receptor bullied out the normal receptor in the cells and quieted their hyperactivity. Mice treated with gene therapy also behaved more like normal, sighted mice.

Ongoing experiments suggest that the brain, too, responds differently once the receptor is blocked, showing activity closer to normal.

While Kramer continues experiments to determine how retinoic acid makes the ganglion cells become hyperactive and how effective the inhibitors are at various stages of retinal degeneration, he is hopeful that the research community will join the effort to repurpose drugs originally developed for cancer into therapies for improving human vision.


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Research shows that losing weight can help prevent or delay the onset of diabetes. While best practice for weight loss often includes decreasing or eliminating calories from alcohol, few studies examine whether people who undergo weight loss treatment report changes in alcohol intake and whether alcohol influences their weight loss.

A new study from the University of Pennsylvania School of Nursing (Penn Nursing) suggests that alcohol consumption may attenuate long-term weight loss in adults with Type 2 diabetes.

In the study, close to 5,000 people who were overweight and had diabetes were followed for four years. One group participated in Intensive Lifestyle Intervention (ILI) and the other in a control group consisting of diabetes support and education. Data showed that participants in the ILI group who abstained from alcohol consumption over the four-year period lost more weight than those who drank any amount during the intervention. Results from the study also showed that heavy drinkers in the ILI group were less likely to have clinically significant weight loss over the four years.

“This study indicates that while alcohol consumption is not associated with short-term weight loss during a lifestyle intervention, it is associated with worse long-term weight loss in participants with overweight or obesity and Type 2 diabetes,” says lead investigator Ariana M. Chao, PhD, CRNP, Assistant Professor of Nursing in the Department of Biobehavioral Health Sciences. “Patients with Type 2 diabetes who are trying to lose weight should be encouraged to limit alcohol consumption.”


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