Category: Ophthalmology

Categories : Implants and Prostheses OphthalmologyTags :

Oxford Researchers Develop Uniquely Shaped Microstent to Combat Glaucoma

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A schematic of the eye’s anterior segment, demonstrating the anatomical placement of the microstent. The stent diverts aqueous humour from the anterior chamber to the suprachoroidal space through the flexible tube, creating a subconjunctival bleb supported by the expanding element. Credit: Yunlan Zhang, Zhong You, Jared Ching.

A team of researchers at the University of Oxford have unveiled a pioneering ‘microstent’ which could revolutionise treatment for glaucoma, a common but debilitating condition. The study has been published in The Innovation, Cell Press.

Glaucoma is a leading cause of vision loss, second only to cataracts. Globally, 7.7 million people were blind or visually impaired due to glaucoma in 2020. The condition can cause irreversible damage to the optic nerve, due to increased pressure within the eyeball. Current treatment options – principally surgery to create openings in the eye or insert tubes to drain fluid – are highly invasive, carry risk of complications, and have limited durability.

‘Our deployable microstent represents a significant advancement in glaucoma treatment,’ said lead author Dr Yunlan Zhang (University of Oxford at the time of the study/University of Texas). ‘Current surgical implants for this type of glaucoma have been shown to have limited long-term effectiveness, being susceptible to failure due to fibrosis (scarring) in the eye.’ 

The new microstent features a unique structural shape that allows it to expand once in the eye. At 200µm, less than a quarter of a millimetre, the stent’s tiny diameter enables it to fit within the needle of a standard hypodermic syringe, for minimally-invasive insertion. Once in place and expanded, the microstent spans the fluid-filled space between the white of the eye and the membrane that covers it.

By supporting this space, the stent reduces the excessive fluid buildup and resulting intraocular pressure in the eye which is responsible for the most common type of glaucoma, primary open-angle glaucoma. Initial trials carried out in rabbits found that the microstents lowered eye pressure in less than a month with minimal inflammation and scarring. Furthermore, the microstent achieved a greater reduction of eye pressure than a standard tubular implant.

This development has the potential to transform the landscape of glaucoma therapy. By offering an enhanced solution in the minimally invasive glaucoma surgery field that combines mechanical innovation with biocompatibility, we hope to improve patient outcomes and quality of life.

Senior co-author Dr Jared Ching (Department of Engineering Science, University of Oxford).

Senior co-author, Professor Zhong You (Department of Engineering Science, University of Oxford) said: ‘Our microstent is made from a durable and super-flexible nickel-titanium alloy called nitinol, renowned for its proven long-term safety for ocular use. Its unique material and structural properties help prevent subsequent movement, improve durability, and ensure long-term efficacy.’

The research team used advanced modelling techniques to guide the microstent’s design and ensure compatibility with the anatomy of the eye. The device’s superelastic properties enable it to accommodate how the eye changes and stretches over time without permanent deformation, enhancing its durability and functionality.

Over half a million people in the UK have glaucoma – 2% of everyone over the age of 40 – and it is one of the most common causes of blindness worldwide. The introduction of this microstent could mark a pivotal step in enhancing treatment efficacy and accessibility.

The study ‘A Novel Deployable Microstent for the Treatment of Glaucoma has been published in The Innovation, Cell Press.

Source: Oxford University

Categories : OphthalmologyTags :

Blinking and Eyelid Function Is Enabled by Complex Control of Muscles

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Discovery could help pave the way for a prosthetic device to restore blink function lost to injury or disease

Muscle activation and movement patterns over time across the upper and lower eyelids, shown under different actions. Credit: Anatomical Engineering Group/UCLA

A blink of an eye is vital to protecting the eye by keeping it from drying out. This simple function seems natural and instantaneous, but is it?

Now, a team of UCLA biomechanical engineers and ophthalmologists has uncovered new details about the muscle that controls blinking, offering a pathway toward developing blink-assisting prostheses. Published in PNAS, the study found that the orbicularis oculi – the muscle that controls eyelid movement – contracts in complex patterns that vary by action and move the eyelid in more than just a simple up-and-down motion.

The researchers studied how this muscle behaves differently across various actions including spontaneous blinks, protective rapid closures and squeezed shut-eye motions.

“The eyelid’s motion is both more complex and more precisely controlled by the nervous system than previously understood,” said study corresponding author Tyler Clites, an assistant professor of mechanical and aerospace engineering at the UCLA Samueli School of Engineering. “Different parts of the muscle activate in carefully timed sequences depending on what the eye is doing. This level of muscle control has never been recorded in the human eyelid. Now that we have this information in rich detail, we can move forward in designing neuroprostheses that help restore natural eyelid function.”

In experiments with volunteers, the researchers looked at five different ways the eyes close:

  • Spontaneous blink: An automatic, unconscious blink that occurs regularly to keep the eye lubricated
  • Voluntary blink: An intentional blink, as when someone is asked to blink on command
  • Reflexive blink: A rapid, involuntary blink triggered to protect the eye from a collision
  • Soft closure: A gentle, slow eyelid descent, similar to the beginning of sleep
  • A forced closure: A deliberate squeezing of the eyelids tightly shut

To record activity in the orbicularis oculi with high precision, an ophthalmic surgeon inserted tiny wire electrodes into the eyelid. The researchers then used a motion-capture system to track eyelid movement in ultraslow motion. These tools allowed the team to measure subtle differences in eyelid movement, including speed, direction, and which part of the muscle initiated the action.

Video of spontaneous blink – dynamic muscle activation patterns and eyelid kinematics. Credit: Anatomical Engineering Group/UCLA

“People can lose the ability to blink due to a stroke, tumour, infection or injury. The condition is painful in the short term and can damage the eyes enough to cause vision loss,” said study co-author Dr Daniel Rootman, an associate professor of ophthalmology at the David Geffen School of Medicine at UCLA and director of the UCLA Orbital Disease Center. “We know that a small electric pulse can stimulate the orbicularis oculi muscle to move, but designing one that works well has been elusive. What we now have is a good roadmap to such a device, including where exactly to place electrodes, how to time them, and how strong the pulse should be. These guidelines could help pave the way for the development and clinical testing of such a device, with the ultimate goal of providing real relief for patients.”

With this fundamental knowledge of eyelid biomechanics in hand, the researchers can now work on refining a prototype neuroprosthesis to assist people with blinking.

“Understanding how the eyelid works is crucial to designing an accurate stimulation pattern for a prosthesis, as well as for diagnostic purposes,” said study first author Jinyoung Kim, a UCLA mechanical engineering doctoral student and member of Clites’ research group, the Anatomical Engineering Group at UCLA. “We are more than excited to bridge this gap and move forward to work with patients who have facial paralysis and help improve their lives.”

Source: UCLA Samueli School of Engineering

Categories : OphthalmologyTags :

Retinal Repair Work is Done by Microglia, not Neutrophils

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Findings have implications for understanding what goes wrong in retinal diseases

Photoreceptor cells in the retina. Credit: Scientific Animations

In a new study from the Flaum Eye Institute and Del Monte Institute for Neuroscience at the University of Rochester, researchers have discovered that the retina responds to damage differently than many other tissues in the body. When photoreceptor cells in the retina are damaged, microglia, or the brain’s immune cells, respond, and the neutrophils are not recruited to help despite passing through nearby blood vessels.

“This finding has high implications for what happens for millions of Americans who suffer vision loss through loss of photoreceptors,” said Jesse Schallek, PhD, associate professor of Ophthalmology and senior author of the study published in eLife. “This association between two key immune cell populations is essential knowledge as we build new therapies that must understand the nuance of immune cell interactions.”

Using adaptive optics imaging, a camera technology developed by the University of Rochester that allows the imaging of single neurons and immune cells inside the living eye, researchers studied the retinas of mice with photoreceptor damage. They found that while both neutrophil and microglia cells are present in the retina, only microglia cells respond to photoreceptor injury, and they do not call upon neutrophils to help repair the photoreceptor damage. Researchers believe this suggests a type of cloaking occurs during retinal injury to protect the retina from a rush of immune cells that could do more harm than good.

“What is remarkable here is that the passing neutrophils are so close to the reactive microglia, and yet they do not signal to them to assist in damage recovery,” said Schallek.

“This is notably different than what is seen in other areas of the body where neutrophils are the first to respond to local damage and mount an early and robust response.”

Source: University of Rochester Medical Center

Categories : New Compounds and Treatments OphthalmologyTags :

Boosting Apolipoprotein-M May Block Age-related Macular Degeneration

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Retina showing reticular pseudodrusen. Although they can infrequently appear in individuals with no other apparent pathology, their highest rates of occurrence are in association with age-related macular degeneration (AMD), for which they hold clinical significance by being highly correlated with end-stage disease sub-types, choroidal neovascularisation and geographic atrophy. Credit: National Eye Institute

A new study from Washington University School of Medicine in St. Louis identifies a possible way to slow or block progression of age-related macular degeneration, a leading cause of blindness in people over age 50. The WashU Medicine researchers and their international collaborators implicated problems with cholesterol metabolism in this type of vision loss, perhaps helping to explain the links between macular degeneration and cardiovascular disease, which both worsen with age.

The new findings, using human plasma samples and mouse models of macular degeneration, suggest that increasing the amount of a molecule called apolipoprotein M (ApoM) in the blood fixes problems in cholesterol processing that lead to cellular damage in the eyes and other organs. Various methods of dialing up ApoM could serve as new treatment strategies for age-related macular degeneration and perhaps some forms of heart failure triggered by similar dysfunctional cholesterol processing.

The study appears June 24 in the journal Nature Communications.

“Our study points to a possible way to address a major unmet clinical need,” said senior author Rajendra S. Apte, MD, PhD, professor of ophthalmology and visual sciences at WashU Medicine. “Current therapies that reduce the chance of further vision loss are limited to only the most advanced stages of macular degeneration and do not reverse the disease. Our findings suggest that developing treatments that increase ApoM levels could treat or even prevent the disease and therefore preserve people’s vision as they age.”

In macular degeneration, doctors can see cholesterol-rich deposits under the retina during an eye exam, according to Apte. In early stages, vision might still be normal, but the deposits increase inflammation and other damaging processes the lead to the gradual loss of central vision. In the most common type, “dry” macular degeneration, the cells in the central part of the retina can be damaged, causing a type of neurodegeneration called geographic atrophy, which is similar to what happens in the brain in conditions such as Alzheimer’s disease. Dry macular degeneration can turn into “wet” macular degeneration, in which abnormal blood vessel growth damages vision.

Geographic atrophy and wet macular degeneration are advanced forms of the disease that are accompanied by vision loss. Although some approved therapies for advanced disease are available, the disease process itself is not reversible at that stage.

A common culprit in eye disease and heart failure

In recent years, evidence has emerged that ApoM can serve as a protective molecule with known anti-inflammatory effects and roles in maintaining healthy cholesterol metabolism. With that in mind, Apte and co-senior author Ali Javaheri, MD, PhD, an assistant professor of medicine, were interested in assessing whether reduced ApoM levels, which fall with age, could be involved in the dysfunctional cholesterol metabolism that is at the root of multiple diseases of aging, including macular degeneration and heart disease. They showed that patients with macular degeneration have reduced levels of ApoM circulating in the blood compared with healthy controls. And past work by Javaheri, a WashU Medicine cardiologist, showed that patients with various forms of heart failure also had reduced levels of ApoM in the blood.

This study revealed that ApoM is a key component in the “good cholesterol” pathways that mop up excess “bad” LDL cholesterol and excrete it via the liver.

Apte and Javaheri’s research suggests that when ApoM is low, cells in the retina and heart muscle can’t correctly metabolise cholesterol deposits and struggle to clear these accumulating lipids. When these lipids build up, it leads to inflammation and cellular damage.

To see if they could reverse the harmful effects of low ApoM, the researchers increased ApoM levels in mouse models of macular degeneration, using genetic modification or plasma transfer from other mice. The mice showed evidence of improved retinal health, improved function of light-sensing cells in the retina and reduced accumulation of cholesterol deposits. The researchers further found evidence that ApoM triggers a signalling pathway that breaks down the cholesterol in cellular compartments called lysosomes, which are known for playing important roles in disposing of cellular waste.

The researchers also found that ApoM must be bound to a molecule called sphingosine-1-phosphate (S1P) to get the beneficial effects of ApoM treatment in the mice.

The findings also could have implications for future interventions that raise ApoM in patients with heart failure.

“One of the exciting things about this collaboration is realising the links between retinal pigment epithelial cells and heart muscle cell, which are both vulnerable to low ApoM,” Javeheri said. “It is possible that the interaction between ApoM and S1P is regulating cholesterol metabolism in both cell types. We look forward to exploring strategies to increase ApoM in ways that could help the eye and the heart maintain healthy cholesterol metabolism over time and stave off two major diseases of aging.”

Source: WashU Medicine

Categories : Diet and Nutrition OphthalmologyTags :

Vitamin Supplements Slow Down the Progression of Glaucoma

On By Peter Van Dyk
Photo by Ksenia Chernaya

A vitamin supplement that improves metabolism in the eye appears to slow down damage to the optic nerve in glaucoma. Promising results have been published in the journal Cell Reports Medicine. The researchers behind the study have now started a clinical trial on patients.

In glaucoma, the optic nerve is gradually damaged, leading to vision loss and, in the worst cases, blindness. High pressure in the eye drives the disease, and eye drops, laser treatment or surgery are therefore used – with varying effect – to lower the pressure in the eye and thus slow down the disease.

Glaucoma researchers have long theorised that the substance homocysteine is somehow relevant to understanding the disease. Now, researchers at Karolinska Institutet have investigated the role of homocysteine in several ways. In the current study, the researchers discovered that when rats with glaucoma were given elevated levels of homocysteine, their disease did not worsen. 

Investigated metabolic pathways

The researchers also found that high levels of homocysteine in the blood of people with glaucoma did not correlate with how quickly the disease progressed, and that glaucoma was not more common in people with a genetic susceptibility to forming high levels of homocysteine. Based on these findings, the researchers concluded that homocysteine does not drive the disease but is a consequence of it.

Since homocysteine is a natural part of the body’s metabolism, the researchers wanted to investigate metabolic pathways involving homocysteine in both rodents and humans with glaucoma. They then saw several abnormalities, the most important of which were metabolic changes linked to the retina’s ability to use certain vitamins. This change meant that metabolism was slowed down locally in the retina – and this played a role in the development of the disease. 

“Our conclusion is that homocysteine is a bystander in the disease process, not a player. Altered homocysteine levels may reveal that the retina has lost its ability to use certain vitamins that are necessary to maintain healthy metabolism. That’s why we wanted to investigate whether supplements of these vitamins could protect the retina”, says co-lead on the paper James Tribble, researcher and assistant professor at the Department of Clinical Neuroscience at Karolinska Institutet.

Promising results lead to clinical trial

In experiments on mice and rats with glaucoma, the researchers gave supplements of the B vitamins B6, B9 and B12, as well as choline. This had a positive effect. In mice that had a slower developing glaucoma, the damage to the optic nerve was completely halted. In rats, which had a more aggressive form of the disease with faster progression, the disease was slowed down. 

In these experiments, eye pressure was left untreated, which the researchers highlight as particularly interesting – it suggests that the vitamin mix affects the disease in a different way than lowering eye pressure does. 

“The results are so promising that we have started a clinical trial, with patients already being recruited at S:t Eriks Eye Hospital in Stockholm”, says James Tribble. 

Both patients with primary open-angle glaucoma (slower progression) and pseudoexfoliation glaucoma (faster progression) are included. 

Read more about the clinical trial here. 

Source: Karolinska Institutet

Categories : OphthalmologyTags :

The Rise in Dry Eye Disease Among Young Adults

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Photo by Steinar Engeland on Unsplash

Researchers at Aston University have called for more advice to be given to young people about preventing dry eye disease, after a study carried out in conjunction with Oslo University Hospital and Sørlandet Hospital Trust in Norway found that 90% of participants had at least one sign of the condition in their eyes.

Dry eye disease occurs when the eyes do not make enough tears, or make poor-quality tears without sufficient lipid or mucus levels which leads to poor tear film stability and rapid evaporation. Sufferers may have gritty feeling eyes, itching or stinging in the eyes, red eyes, sensitivity to light and blurry vision. There are several risk factors for dry eye disease, including stress and wearing contact lenses. It is also more prevalent in females. In the 18-25 age group, a major risk factor is screen use.

The research, following 50 18-25-year-olds over time, was led by Dr Rachel Casemore at Aston University School of Optometry and is the first of its kind. It was published in The Ocular Surface. The researchers looked for symptoms of dry eye disease in the participants, studied lifestyle factors, and followed up with participants one year on to find out if there had been any progression of the condition.

The initial study showed that 56% of participants had dry eye disease, while 90% had at least one symptom of the condition. Around half of the participants in the study had lost at least 25% of a type of gland in the eye called the meibomian gland. These glands produce the outer lipid layer of the eye’s tear film, which is responsible for preventing evaporation of tears, and therefore keeps the tear film stable and the eye moist. One year on, the researchers found that there had been significant progression of dry eye disease in the study participants.

Additionally, the researchers found correlation found between how long the study group used screens and signs of dryness on the eye surface. The average screen use of participants was eight hours per day.

The researchers concluded that the evidence of dry eye disease symptoms and progression in the young adults in their study shows the need for early detection of potential signs, and the identification of those who may go on to develop dry eye disease. These individuals can then be advised on managing the condition before progression.

The progression and development of dry eye disease can be slowed by various methods. Dr Casemore says that the simplest ways are to take regular screen breaks, to carry out blink exercises to ensure the release of oils from the meibomian glands and to keep hydrated. A healthy, balanced diet, including sources of omega-3 fatty acids, such as oily fish, is also important, as is regular sleep patterns.

Dr Casemore suggests that those with irregular sleep patterns, such as those caused by sleep disorders or anxiety, should seek advice. People who wear contact lenses need to ensure they get regular check-ups to ensure optimum fitting, and that they adhere to their replacement schedule, wearing time schedule, cleaning regimes and safety advice, such as no sleeping, showering or swimming in contact lenses.

Dr Casemore said:

“It is concerning to note the increasing prevalence of dry eye disease signs and symptoms in young adults, which has been referred to as a ‘lifestyle epidemic’ by some researchers. Eye care practitioners are well placed to identify the clinical indicators of dry eye disease and counsel young adults around modifiable risk factors, such as screen use habits, sleeping habits, contact lens use, diet, blinking patterns, and management of stress levels.

“Our future research aims to continue investigation of the potential tear and meibomian gland oil biomarkers which were identified during the study and further explore the effect of diet on dry eye disease development.”

Source: Aston University

Categories : Mental Health OphthalmologyTags :

Genetic Schizophrenic Susceptibility Could Show up in the Retina

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Photoreceptor cells in the retina. Credit: Scientific Animations

Could the eyes, which are directly connected to the brain, hold clues to brain changes? An international team of researchers led by the University of Zurich and the University Hospital of Psychiatry Zurich has now tackled this very question. In their study, published in Nature Mental Health, the researchers examined whether changes in our nerve connections are linked to a genetic risk for schizophrenia, as impaired neural information processing is one of the main characteristics of the disorder.

Previous studies suggest that schizophrenia not only reduces volume of grey matter in the brains of those affected, but that it also leads to loss of retinal tissue. But whether these changes are the cause of schizophrenia or a consequence of the disorder has remained unanswered. Retinal health could also be affected by schizophrenia itself, for example, through antipsychotic medication, lifestyle factors or diabetes.

Extensive use of data from healthy individuals

“To investigate whether the risk of developing schizophrenia has an effect on the central nervous system, we examined tens of thousands of healthy individuals,” says Finn Rabe, first author of the study and postdoc at the University of Zurich. “We then calculated polygenic risk scores for each individual.”

The researchers were able to use extensive genetic and retinal data taken from the UK Biobank, a large biomedical database containing data from over half a million people. “You could say that the scale of the UK Biobank’s data has revolutionised biomedical research,” the researcher adds.

Thin retina, elevated risk

The study shows that higher genetic susceptibility to schizophrenia is indeed associated with thinner retinas. The effects are small, though, and can only be reliably demonstrated in large-scale studies. One of the study’s findings is that, unlike changes in the brain, changes in the retina are easy to detect using non-invasive and inexpensive retinal measurements. Thanks to optical coherence tomography, which can be described as a kind of ultrasound for the eye, retinal thickness can be measured in minutes.

This offers a promising outlook for prevention. “Our study shows the potential of using optical coherence tomography in clinical practice. But large-scale longitudinal studies are needed to examine how useful it will be for prevention,” says Finn Rabe.

Perspectives for new therapies

Another key finding of the study concerns genetic variants associated with inflammatory processes in the brain. These may also contribute to structural changes in the retina. The study thus offers further support for the inflammation hypothesis of schizophrenia, ie, the idea that inflammatory processes contribute to the development or progression of the disorder. “If this hypothesis is confirmed, inflammation could be interrupted by medication, potentially enabling us to improve treatment possibilities in the future,” says Rabe.

Source: University of Zurich

Categories : New Compounds and Treatments OphthalmologyTags :

Goldeneye: Research on Restoring Eyesight with Gold Nanoparticles

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Retina showing reticular pseudodrusen. Although they can infrequently appear in individuals with no other apparent pathology, their highest rates of occurrence are in association with age-related macular degeneration (AMD), for which they hold clinical significance by being highly correlated with end-stage disease sub-types, choroidal neovascularisation and geographic atrophy. Credit: National Eye Institute

A new study by Brown University researchers suggests that gold nanoparticles might one day be used to help restore vision in people with macular degeneration and other retinal disorders. 

In a study published in the journal ACS Nano and supported by the National Institutes of Health, the research team showed that nanoparticles injected into the retina can successfully stimulate the visual system and restore vision in mice with retinal disorders. The findings suggest that a new type of visual prosthesis system in which nanoparticles, used in combination with a small laser device worn in a pair of glasses or goggles, might one day help people with retinal disorders to see again. 

“This is a new type of retinal prosthesis that has the potential to restore vision lost to retinal degeneration without requiring any kind of complicated surgery or genetic modification,” said Jiarui Nie, research leader and now a postdoctoral researcher. “We believe this technique could potentially transform treatment paradigms for retinal degenerative conditions.” 

Nie performed the work while working in the lab of Jonghwan Lee, an associate professor in Brown’s School of Engineering and a faculty affiliate at Brown’s Carney Institute for Brain Science, who oversaw the work and served as the study’s senior author. 

Retinal disorders like macular degeneration and retinitis pigmentosa affect millions of people in the U.S. and around the world. These conditions damage light-sensitive cells in the retina called photoreceptors — the “rods” and “cones” that convert light into tiny electric pulses. Those pulses stimulate other types of cells further up the visual chain called bipolar and ganglion cells, which process the photoreceptor signals and send them along to the brain. 

This new approach uses nanoparticles injected directly into the retina to bypass damaged photoreceptors. When infrared light is focused on the nanoparticles, they generate a tiny amount of heat that activates bipolar and ganglion cells in much the same way that photoreceptor pulses do. Because disorders like macular degeneration affect mostly photoreceptors while leaving bipolar and ganglion cells intact, the strategy has the potential to restore lost vision. 

In this new study, the research team tested the nanoparticle approach in mouse retinas and in living mice with retinal disorders. After injecting a liquid nanoparticle solution, the researchers used patterned near-infrared laser light to project shapes onto the retinas. Using a calcium signal to detect cellular activity, the team confirmed that the nanoparticles were exciting bipolar and ganglion cells in patterns matched the shapes projected by the laser.

The experiments showed that neither the nanoparticle solution nor the laser stimulation caused detectable adverse side effects, as indicated by metabolic markers for inflammation and toxicity. Using probes, the researchers confirmed that laser stimulation of the nanoparticles caused increased activity in the visual cortices of the mice — an indication that previously absent visual signals were being transmitted and processed by the brain. That, the researchers say, is a sign that vision had been at least partially restored, a good sign for potentially translating a similar technology to humans. 

For human use, the researchers envision a system that combines the nanoparticles with a laser system mounted in a pair of glasses or goggles. Cameras in the goggles would gather image data from the outside world and use it to drive the patterning of an infrared laser. The laser pulses would then stimulate the nanoparticles in people’s retinas, enabling them to see. 

The approach is similar to one that was approved by the Food and Drug Administration for human use a few years ago. The older approach combined a camera system with a small electrode array that was surgically implanted in the eye. The nanoparticle approach has several key advantages, according to Nie.

For starters, it’s far less invasive. As opposed to surgery, “an intravitreal injection is one of the simplest procedures in ophthalmology,” Nie said. 

There are functional advantages as well. The resolution of the previous approach was limited by the size of the electrode array — about 60 square pixels. Because the nanoparticle solution covers the whole retina, the new approach could potentially cover someone’s full field of vision. And because the nanoparticles respond to near-infrared light as opposed to visual light, the system doesn’t necessarily interfere with any residual vision a person may retain.   

More work needs to be done before the approach can be tried in a clinical setting, Nie said, but this early research suggests that it’s possible.

“We showed that the nanoparticles can stay in the retina for months with no major toxicity,” Nie said of the research. “And we showed that they can successfully stimulate the visual system. That’s very encouraging for future applications.”

Source: Brown University

Categories : OphthalmologyTags :

Tests on Animals Demonstrate that New Eye Drops can Slow Vision Loss

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Model of PEDF protein alongside the 17-mer and H105A peptides. Amino acid 105, which is changed from histidine in PEDF and the 17-mer peptide to alanine in the H105A peptide, is shown in green.

Researchers at the National Institutes of Health (NIH) have developed eye drops that extend vision in animal models of a group of inherited diseases that lead to progressive vision loss in humans, known as retinitis pigmentosa. The eye drops contain a small fragment derived from a protein made by the body and found in the eye, known as pigment epithelium-derived factor (PEDF). PEDF helps preserve cells in the eye’s retina. A report on the study is published in Communications Medicine.

“While not a cure, this study shows that PEDF-based eye drops can slow progression of a variety of degenerative retinal diseases in animals, including various types of retinitis pigmentosa and dry age-related macular degeneration (AMD),” said Patricia Becerra, PhD, chief of NIH’s Section on Protein Structure and Function at the National Eye Institute and senior author of the study. “Given these results, we’re excited to begin trials of these eye drops in people.”

All degenerative retinal diseases have cellular stress in common. While the source of the stress may vary—dozens of mutations and gene variants have been linked to retinitis pigmentosa, AMD, and other disorders—high levels of cellular stress cause retinal cells to gradually lose function and die. Progressive loss of photoreceptor cells leads to vision loss and eventually blindness.

Previous research from Becerra’s lab revealed that, in a mouse model, the natural protein PEDF can help retinal cells stave off the effects of cellular stress. However, the full PEDF protein is too large to pass through the outer eye tissues to reach the retina, and the complete protein has multiple functions in retinal tissue, making it impractical as a treatment. To optimize the molecule’s ability to preserve retinal cells and to help the molecule reach the back of the eye, Becerra developed a series of short peptides derived from a region of PEDF that supports cell viability. These small peptides can move through eye tissues to bind with PEDF receptor proteins on the surface of the retina.

Model of PEDF protein alongside the 17-mer and H105A peptides. Amino acid 105, which is changed from histidine in PEDF and the 17-mer peptide to alanine in the H105A peptide, is shown in green.

In this new study, led by first author Alexandra Bernardo-Colón, Becerra’s team created two eye drop formulations, each containing a short peptide. The first peptide candidate, called “17-mer,” contains 17 amino acids found in the active region of PEDF. A second peptide, H105A, is similar but binds more strongly to the PEDF receptor. Peptides applied to mice as drops on the eye’s surface were found in high concentration in the retina within 60 minutes, slowly decreasing over the next 24 to 48 hours. Neither peptide caused toxicity or other side effects.

When administered once daily to young mice with retinitis pigmentosa-like disease, H105A slowed photoreceptor degeneration and vision loss. To test the drops, the investigators used specially bred mice that lose their photoreceptors shortly after birth. Once cell loss begins, the majority of photoreceptors die in a week. When given peptide eye drops through that one-week period, mice retained up to 75% of photoreceptors and continued to have strong retinal responses to light, while those given a placebo had few remaining photoreceptors and little functional vision at the end of the week.

“For the first time, we show that eye drops containing these short peptides can pass into the eye and have a therapeutic effect on the retina,” said Bernardo-Colón. “Animals given the H105A peptide have dramatically healthier-looking retinas, with no negative side effects.”

A variety of gene-specific therapies are under development for many types of retinitis pigmentosa, which generally start in childhood and progress over many years. These PEDF-derived peptide eye drops could play a crucial role in preserving cells while waiting for these gene therapies to become clinically available.

To test whether photoreceptors preserved through the eye drop treatment are healthy enough for gene therapy to work, collaborators Valeria Marigo, PhD and Andrea Bighinati, PhD, University of Modena, Italy, treated mice with gene therapy at the end of the week-long eye drop regimen. The gene therapy successfully preserved vision for at least an additional six months.  

To see whether the eye drops could work in humans – without actually testing in humans directly – the researchers worked with Natalia Vergara, PhD, University of Colorado Anschutz, Aurora, to test the peptides in a human retinal tissue model of retinal degeneration. Grown in a dish from human cells, the retina-like tissues were exposed to chemicals that induced high levels of cellular stress. Without the peptides, the cells of the tissue model died quickly, but with the peptides, the retinal tissues remained viable. These human tissue data provide a key first step supporting human trials of the eye drops.

Source: NIH/National Eye Institute

Categories : Neurology OphthalmologyTags :

The Pupil as a Window into the Sleeping Brain

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The eye of the sleeping subject was kept open with a special fixation device to record the pupil movements for several hours.  (Image: Neural Control of Movement Lab / ETH Zurich)

For the first time, researchers have been able to observe how the pupils react during sleep over a period of several hours. A look under the eyelids showed them that more happens in the brain during sleep than was previously assumed.

While eyes are typically closed in sleep, there is a flurry of activity taking place beneath the eyelids: a team of researchers, led by principal investigators Caroline Lustenberger, Sarah Meissner and Nicole Wenderoth from the Neural Control of Movement Lab at ETH Zurich, have observed that the size of the pupil fluctuates constantly during sleep. As they report in Nature Communications, sometimes it increases in size, sometimes it decreases; sometimes these changes occur within seconds, other times over the course of several minutes.

“These dynamics reflect the state of arousal, or the level of brain activation in regions that are responsible for sleep-wake regulation,” says Lustenberger. “These observations contradict the previous assumption that, essentially, the level of arousal during sleep is low.”

Instead, these fluctuations in pupil size show that even during sleep, the brain is constantly switching between a higher and lower level of activation. These new findings also confirm for humans what other research groups have recently discovered in studies on rodents, who also exhibit slow fluctuations in the activation level (known in the field as arousal).

New method for an old mystery

The regions of the brain which control the activation level are situated deep within the brainstem, making it previously difficult to directly measure these processes in humans during sleep. Existing methods are technically demanding and have not yet been established in this context. The ETH researchers’ study therefore relies on pupil measurements. Pupils are known to indicate the activation level when a person is awake. They can therefore be used as markers for the activity in regions situated deeper within the brain.

The ETH researchers developed a new method for examining the changes in people’s pupils while asleep: using a special adhesive technique and a transparent plaster, they were able to keep the eyes of the test subjects open for several hours.

“Our main concern was that the test subjects would be unable to sleep with their eyes open. But in a dark room, most people forget that their eyes are still open and they are able to sleep,” explains the study’s lead author, Manuel Carro Domínguez, who developed the technique.

Analysis of the data showed that pupil dynamics is related not just to the different stages of sleep, but also to specific patterns of brain activity, such as sleep spindles and pronounced deep sleep waves – brain waves that are important for memory consolidation and sleep stability. The researchers also discovered that the brain reacts to sounds with varying degrees of intensity, depending on the level of activation, which is reflected in the size of the pupil.

A central regulator of the activation level is a small region in the brainstem, known as the locus coeruleus. In animals, scientists have been able to show that this is important for the regulation of sleep stages and waking. The ETH researchers were unable to prove in this study whether the locus coeruleus is indeed directly responsible for pupil changes. “We are simply observing pupil changes that are related to the level of brain activation and heart activity,” Lustenberger explains.

In a follow-up study, the researchers will attempt to influence the activity of the locus coeruleus using medication, so that they can investigate how this affects pupil dynamics. They hope to discover whether this region of the brain is in fact responsible for controlling the pupils during sleep, and how changes in the level of activation affect sleep and its functions.

Using pupillary dynamics to diagnose illnesses

Understanding pupil dynamics during sleep could also provide important insights for the diagnosis and treatment of sleep disorders and other illnesses. The researchers therefore want to investigate whether pupil changes during sleep can provide indications of dysfunctions of the arousal system. These include disorders such as insomnia, post-traumatic stress disorder and possibly Alzheimer’s. “These are just hypotheses that we want to investigate in the future,” says Lustenberger.

Another goal is to make the technology usable outside of sleep laboratories, such as in hospitals where it could help to monitor waking in coma patients or to diagnose sleep disorders more accurately. The pupil as a window onto the brain could thus pave the way for new opportunities in sleep medicine and neuroscience.

Source: ETH Zurich