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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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09/Oct/2020

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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27/Aug/2020

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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14/Feb/2020

February Is Age-Related Macular Degeneration (AMD) / Low-Vision Awareness Month

What is Macular Degeneration?

Age-Related Macular Degeneration (AMD) is a relatively common eye condition. It is the leading cause of vision loss in adults 55 and over. It affects more than 10 million Americans – more than both glaucoma and cataracts combined.

Some people experience gradual vision loss over a long time, while others have a progressive form of the disease, which can cause loss of vision in one eye or both. As the disease progresses, objects appear dimmer and dark spots may develop in the central field of vision.

Who’s at risk?

While age is a significant factor in developing AMD, there are some additional risk factors.

  • Race – AMD is more frequently diagnosed in Caucasians than Hispanics/Latinos or African Americans.
  • Family History/Genetics – If someone has a family history of AMD, they are at higher risk for developing this degenerative disease. Researcher has identified approximately 20 genes that may influence the development of AMD; however, many more genetic markers are suspected. There are no genetic tests that can predict with 100% certainty who will develop AMD.
  • Smoking – Smoking more than doubles your risk of developing AMD.

It is caused by a deterioration of the Macula (the central part of the retina), which is the inside back layer of your eye. The macula is also responsible for our ability to drive a car, read, see fine detail, and recognize faces and colors.

Much like camera film, the macula is a light- sensitive area that collects highly detailed images. Those images are then sent to, and processed by, the brain. When the macula starts to deteriorate, the images fail to process correctly.

As deterioration continues, people may experience blurred or wavy vision and if it continues, the entire central vision field may be lost. People that suffer from advanced macular degeneration may be considered legally blind.

Currently, Macular Degeneration is incurable.

While the causes of macular degeneration are not clearly understood. Age-related reasons are a combination of both hereditary and environmental influences.

The disease is most prevalent in people over the age of 55. Prevention of environmental influences is one way of reducing your risk. As environmental influences to AMD appear to be cumulative, protection and prevention should begin as early as possible. Ask the knowledgeable folks at Goodrich Optical what can be done to protect your precious eyesight

Scientists are working hard to better understand this disease. Without further advancement, it is estimated that by 2050, nearly 22 million Americans will suffer from macular degeneration.[/vc_column_text][/vc_column][/vc_row]


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