Young Scientist Helps Identify Cause of Widespread Eye Disease

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Posted on 27th December 2012 by Pacific ClearVision Institute in General |Retina

Branch retinal vein occlusion — blockage of the blood vessels that channel blood from the retina — is a common eye disease. A type of blood clot in the eye, the disease causes reduced vision, and people with the disease also typically have an increased risk of hypertension, diabetes and other serious conditions. A young scientist from the University of Copenhagen has made a significant contribution to finding the cause of the disease.

A team of researchers at the University of Copenhagen, Glostrup Hospital and several other ophthalmology departments at Danish hospitals have now shown that it is highly probable that thickening of the arterial walls is behind the common eye disease known as branch retinal vein occlusion — a type of blood clot in the eye that blocks the vessels that transport blood from the retina. The disease leads to reduced vision and affects more than 14 million people worldwide.

“Our new results indicate that branch retinal vein occlusion is caused by thickening of the arterial wall. This makes it crucial for doctors to treat patients diagnosed with the disease with medicine to lower blood pressure in order to prevent blood clots from forming in the heart and brain. Branch retinal vein occlusion is often a sign of increased risk of blood clots in other parts of the body,” explains Mette Bertelsen, PhD student at the University of Copenhagen.

Targeted treatment

Mette Bertelsen, head of the research project, and her colleagues photographically verified the diagnosis of branch retinal vein occlusion in 1168 people. They identified the patients’ other diseases with the help of Danish national registries and compared the data to that of 116.800 healthy people.

By looking at the illness and mortality statistics of Danes diagnosed with a blood clot in the retina’s main blood vessels, both before and after the occurrence of the retinal blood clot, Mette Bertelsen and her colleges has now shown that while these patients show a higher frequency of arterial disease in the heart and brain, they do not display a higher frequency of venous disease. This new knowledge, which has been published in the British Medical Journal, means that disease prevention and treatment of these patients should be targeted at hypertension, diabetes and atherosclerosis, while doctors can save patients from unnecessary treatment with anticoagulants.

Thickened arteries the villains

Doctors have long debated the three most likely theories about what causes branch retinal vein occlusion. Discussion centres on whether the disease is due to a) conditions in the veins that cause blood clots, b) a change in the composition of the blood, or c) blockage of the vein due to compression from an adjacent artery that has thickened and thus compresses the vein and hinders blood flow.

“To understand what is actually happening, it can be helpful to picture a garden hose that has been squeezed by a larger hose, cutting off the water supply. That is essentially what happens when a vein is compressed by a thickened artery. Clearly, the consequences can be serious,” explains Mette Bertelsen. She adds that no one knows exactly how many Danes suffer from branch retinal vein occlusion, but that more than 14 million people have the disease worldwide.

Two Novel Treatments for Retinitis Pigmentosa Move Closer to Clinical Trials

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Posted on 27th December 2012 by Pacific ClearVision Institute in General |Retina

Two recent experimental treatments — one involving skin-derived induced pluripotent stem (iPS) cell grafts, the other gene therapy — have been shown to produce long-term improvement in visual function in mouse models of retinitis pigmentosa (RP), according to the Columbia University Medical Center (CUMC) scientists who led the studies. At present, there is no cure for RP, the most common form of inherited blindness.

“While these therapies still need to be refined, the results are highly encouraging,” said Stephen H. Tsang, MD, PhD, associate professor of pathology & cell biology and of ophthalmology at Columbia University Medical Center and an ophthalmologist at NewYork-Presbyterian Hospital/CUMC, the leader of both studies. “We’ve never seen this type of improvement in retinal function in mouse models of RP. We hope we may finally have something to offer patients with this form of vision loss.”

The stem cell study was published in the journal Molecular Medicine. The gene therapy study was published in Human Molecular Genetics.

RP encompasses a group of inherited eye diseases that cause progressive loss of photoreceptor cells, specialized neurons found in the retina. While RP can appear during infancy, the first symptoms typically appear in early adulthood, beginning with night blindness. As the disease progresses, affected individuals lose peripheral vision. In later stages, RP destroys photoreceptors in the macula, which is responsible for fine central vision. Mutations in at least 50 genes have been found to cause the disease, which affects about 1.5 million people worldwide.

In the Molecular Medicine study, the CUMC researchers tested the long-term safety and efficacy of using iPS cell grafts to restore visual function in a mouse model of RP. Like embryonic stem cells, iPS cells are “pluripotent” — that is, they are capable of developing into any cell type. However, iPS cells are not derived from embryos but from adult cells, in this case from human skin cells. The cells were administered, via injection directly underneath the retina, when the mice were five days old.

The iPS cells assimilated into the host retina without disruption, and none of the mice receiving transplants developed tumors over their lifetimes, the researchers reported. The iPS cells were found to express markers specific to retinal pigmented epithelium (the cell layer adjacent to the photoreceptor layer), showing that they had the potential to develop into functional retinal cells. Using electroretinography, a standard method for measuring retinal function, the researchers found that the visual function of the mice improved after treatment and the effect was long lasting. “This is the first evidence of lifelong neuronal recovery in an animal model using stem cell transplants, with vision improvement persisting throughout the lifespan,” said Dr. Tsang.

In 2011, the FDA approved clinical trials of embryonic stem cell transplants for the treatment of macular degenerations, but such therapy requires immunosuppression. “Our study focused on patient-specific iPS cells, which offer a compelling alternative,” said Dr. Tsang. “The iPS cells can provide a potentially unlimited supply of cells for functional rescue and optimization. Also, since they would come from the patient’s own body, immunosuppression would not be necessary to prevent rejection after transplantation.”

In theory, iPS cell transplants could also be used to treat age-related macular degeneration, the leading cause of vision loss among older adults, said Dr. Tsang.

In the Human Molecular Genetics study, the CUMC researchers tested whether gene therapy could be used to improve photoreceptor survival and neuronal function in mice with RP caused by a mutation to a gene called phosphodiesterase-alpha (Pde6?) — a common form of the disease in humans. To treat the mice, the researchers used adeno-associated viruses (AAV) to ferry correct copies of the gene into the retina. The AAV were administered by a single injection in one eye, with the other eye serving as a control.

When the mice were examined at six months of age (over one-third of the mouse lifespan), photoreceptor cells were found in the treated eyes but not in the untreated eyes, the researchers reported. More important, the treated eyes showed functional visual responses, while the untreated eyes had lost all vision.

“These results provide support that RP due to PDE6? deficiency in humans is also likely to be treatable by gene therapy,” said Dr. Tsang.

CUMC and its teaching-hospital affiliate, NewYork-Presbyterian Hospital, are part of an international consortium that was recently formed to bring this PDE6A gene therapy to patients. Pending FDA approval, Phase I/II clinical trials could begin within a year.

Eyes May Provide a Look Into Multiple Sclerosis Progression

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Posted on 27th December 2012 by Pacific ClearVision Institute in General |Retina

New research suggests that thinning of a layer of the retina in the eyes may show how fast multiple sclerosis (MS) is progressing in people with the disease. The study is published in the Jan. 1, 2013, online issue of Neurology®, the medical journal of the American Academy of Neurology.

“This study suggests that retinal thinning, measured by in-office eye scans, called OCT, may occur at higher rates in people with earlier and more active MS,” said Robert Bermel, MD, with the Cleveland Clinic Mellen Center for MS and a member of the American Academy of Neurology, who wrote an accompanying editorial.

For the study, 164 people with MS from the Johns Hopkins MS Center, including 59 who had no disease activity, underwent eye scans that measured thinning of a portion of their retinas every six months for an average of 21 months. Participants were also given MRI brain scans at the start of the study and yearly.

The study found that people with MS relapses had 42 percent faster thinning than people with MS who had no relapses. People with MS who had inflammatory lesions called gadolinium-enhancing lesions experienced 54 percent faster thinning and those with new T2 lesions had 36 percent faster thinning than MS patients without these features of MRI activity.

People whose level of disability worsened during the study experienced 37 percent more thinning than those who had no changes in their level of disability, and those who had the disease less than five years showed 43 percent faster thinning than those who had the disease more than five years.

“As more therapies are developed to slow the progression of MS, testing retinal thinning in the eyes may be helpful in evaluating how effective those therapies are,” said study author Peter Calabresi, MD, with Johns Hopkins University School of Medicine in Baltimore and a Fellow of the American Academy of Neurology.

The study was supported by the National Multiple Sclerosis Society, the National Eye Institute and Braxton Debbie Angela Dillon and Skip Donor Advisor Fund.

Prevalence of Visual Impairment in US Increases

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Posted on 27th December 2012 by Pacific ClearVision Institute in General

The prevalence of nonrefractive visual impairment (not due to need for glasses) in the U.S. has increased significantly in recent years, which may be partly related to a higher prevalence of diabetes, an associated risk factor, according to a study in the December 12 issue of JAMA.

“It is estimated that more than 14 million individuals in the United States aged 12 years and older are visually impaired (<20/40). Of these cases, 11 million are attributable to refractive error. In the United States, the most common causes of nonrefractive visual impairment are age-related macular degeneration, cataract, diabetic retinopathy, glaucoma, and other retinal disorders,” according to background information in the article. Previous studies have shown that visual impairment is common in persons with diabetes. “The prevalence of diagnosed diabetes has increased among adults in recent years, rising from 4.9 percent in 1990 to 6.5 percent in 1998, 7.9 percent in 2001, 10.7 percent in 2007, and 11.3 percent in 2010.”

Fang Ko, M.D., of the Johns Hopkins University School of Medicine, Baltimore, and colleagues conducted a study to assess the prevalence of nonrefractive visual impairment and factors associated with risk of visual impairment. The study included data from the National Health and Nutrition Examination Survey (NHANES), a representative sample of the U.S. population. In 1999-2002 and 2005-2008, 9,471 and 10,480 participants 20 years of age or older received questionnaires, laboratory tests, and physical examinations. Visual acuity of less than 20/40 aided by autorefractor (a device for measuring a person’s refractive error) was classified as nonrefractive visual impairment.

The researchers found that prevalence of nonrefractive visual impairment increased 21 percent, from 1.4 percent in 1999-2002 to 1.7 percent in 2005-2008; and increased 40 percent among non-Hispanic whites 20-39 years of age, from 0.5 percent to 0.7 percent. In analysis among all participants, factors associated with nonrefractive visual impairment included older age, poverty, lower education level, and diabetes diagnosed 10 or more years ago. Among these risk factors, only the latter has increased in prevalence between the 2 time periods considered. Prevalence of diabetes with 10 or more years since diagnosis increased 22 percent overall from 2.8 percent to 3.6 percent; and 133 percent among non-Hispanic whites 20-39 years of age, from 0.3 percent to 0.7 percent.

“We report a previously unrecognized increase of visual impairment among U.S. adults that cannot be attributed to refractive error,” the authors write. “If the current finding becomes a persisting trend, it could result in increasing rates of disability in the U.S. population, including greater numbers of patients with end-organ diabetic damage who would require ophthalmic care. These results have important implications for resource allocation in the debate of distribution of limited medical services and funding. Continued monitoring of visual disability and diabetes, as well as additional research addressing causes, prevention, and treatment, is warranted.”

Soothing Sounds During Cataract Surgery Reduces Patient Anxiety

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Posted on 5th December 2012 by Pacific ClearVision Institute in Cataracts |General

New research shows that the use of an audio therapy known as binaural beats can significantly reduce patients’ anxiety during cataract surgery. The 141-patient study, conducted in Thailand, is the first of its kind in cataract surgery, which is one of the most frequently performed procedures worldwide, with more than 3 million performed annually in the United States.

The research is being presented today at the 116th Annual Meeting of the American Academy of Ophthalmology, jointly conducted this year with the Asia-Pacific Academy of Ophthalmology.

Binaural beat audio therapy consists of two tones that are each pitched at a specific, slightly different frequency, with each tone delivered to a separate ear via headphones. The technique evokes alpha-frequency brainwaves, a state that is linked to relaxation and reduced perception of fear and pain. In this study, the researchers combined binaural beats with soothing music and nature soundscapes that included ocean and forest sounds, to provide a pleasant, familiar experience for patients. (Listen to a sample clip here; use headphones to experience the binaural beat effect.)

The study was conducted using three groups, each consisting of 47 patients, matched for age, gender, cataract type, and other health factors. Patients who listened to a binaural beats-music mix before, during and after the procedure had less anxiety and slower heart rate, compared with the control group patients who do not receive the therapy.

Systolic blood pressure was also significantly reduced in both the binaural beats-music mix patient group and a second patient group who listened to music only. Control group patients heard the usual sounds that occur in a surgical suite. All patients were assessed before and after surgery using the State-Trait Anxiety scale, a standard test used to diagnose anxiety. Their heart rate and blood pressure were also measured before and after surgery.

The research team focused on cataract surgery because it is usually done under local anesthesia, with the patient awake and continuously exposed to unfamiliar, potentially upsetting sounds such as surgical machinery and conversations between the surgeon and staff. Although the procedure is highly effective and safe, patients may be worried about whether their vision and quality of life will be improved or reduced after the surgery. (Click here to see how cataracts affect vision.) The results were consistent with the finding of previous research on the use of the therapy reducing anxiety in general surgery patients.

“As populations in many parts of the world grow older, it’s increasingly important for ophthalmologists to explore new ways to improve patient care for seniors,” said Pornpattana Vichitvejpaisal, M.D., of Chiang Mai University, Thailand, who led the research. “Our study shows significant emotional and physiological benefits from adding binaural beats to music therapy for cataract surgery patients. This provides a simple, inexpensive way to improve patients’ health outcomes and satisfaction with their care.”

Dr. Vichitvejpaisal referenced one of his study participants who reported that during her first cataract surgery, she was afraid from the moment she entered the surgical suite. Though she’d been told it wouldn’t take long, the surgery seemed to drag on endlessly. Receiving sound therapy during her second surgery dramatically changed her experience from start to finish. She said that she felt very little anxiety, and that the surgery was over before she knew it.

Ultra-Small Drainage Device May Replace Eye Drop Medications for Some Glaucoma Patients

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Posted on 5th December 2012 by Pacific ClearVision Institute in General |Retina

A tiny medical device no larger than an eyelash may significantly reduce eye pressure in glaucoma patients and allow some to stop using eye-drop medications, according to year-one clinical trial results for the device. Results of the HYDRUS I clinical trial, which indicate successful control of eye pressure in all study participants, will be presented November 13 at the 116th Annual Meeting of the American Academy of Ophthalmology, jointly conducted this year with the Asia-Pacific Academy of Ophthalmology.

The Hydrus stent is one of several promising mini-drainage devices now in clinical trials in the United States and other countries. If future trials confirm micro-stents’ effectiveness, they could someday help protect millions of glaucoma patients from vision loss or blindness.

Open-angle glaucoma, the most common form of the disease, affects nearly three million people in the U.S and 60 million worldwide. (Click here to see how glaucoma can affect vision.) Though it is a multifactorial disease, currently the only proven way to prevent vision loss is by reducing intraocular pressure (IOP). The treatment choices are effective but less than ideal, as some patients may not use eye drop medications consistently enough to control their IOP, while others simply don’t respond to the drugs. Surgical procedures to open blocked drainage channels or implant larger stents, which are used only for patients with advanced glaucoma, carry risks of infection, bleeding, deterioration of other parts of the eye, and vision loss.

In this particular study of 69 patients suffering from mild to moderate open-angle glaucoma, IOP was reduced to acceptable levels in 100 percent of participants after they received minimally invasive stent implant surgery. In 40 patients the stent was placed during cataract surgery, a procedure that also reduces IOP. Twenty-nine patients had the Hydrus stent placed without cataract surgery to assess whether the stent would be effective on its own. No significant complications occurred in either patient group. At the six-month follow up, 85 percent of combined surgery and 70 percent of stent-only patients no longer needed eye drop medications to control their IOP. Reductions in IOP were consistent among all patients and remained stable at the one year follow up.

“So far, mini-stents appear to have important advantages in that they allow us to treat open-angle glaucoma at earlier stages and with lower complication risk,” said Thomas W. Samuelson, M.D., a glaucoma specialist with Minnesota Eye Consultants, who served as the HYDRUS I trial’s medical monitor. “If the devices can effectively control IOP over many years, it would be a real breakthrough in combating this blinding disease.”

Dr. Samuelson cited the experience of an 81- year-old retired neurosurgeon who had tried multiple glaucoma medications, then had a drainage procedure called a trabeculoplasty, but couldn’t achieve safe IOP levels. In 2010, the Hydrus was implanted in his right eye during cataract surgery, followed by the same surgery in his left eye a year later. A follow-up exam two months ago, confirmed that his IOP levels remained acceptably low in both eyes, without the use of eye drops.

A number of similar mini-stents, including the MIDI Arrow, Aquecentesis, and Transcend are now in development or clinical trials. The iStent was recently approved by the U.S. Food and Drug Administration for use in conjunction with cataract surgery. All of the stents work by providing a new drainage channel for the eye’s aqueous fluid, circumventing the patient’s own clogged or blocked channels. They vary in design, materials and implant site within the eye. Despite encouraging initial results, it will be several years before the long-term safety, efficacy and durability of this treatment approach can be fully confirmed.

Blind Patient Reads Words Stimulated Directly Onto Retina: Neuroprosthetic Device Uses Implant to Project Visual Braille

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Posted on 5th December 2012 by Pacific ClearVision Institute in General |Retina

For the very first time researchers have streamed braille patterns directly into a blind patient’s retina, allowing him to read four-letter words accurately and quickly with an ocular neuroprosthetic device. The device, the Argus II, has been implanted in over 50 patients, many of who can now see color, movement and objects. It uses a small camera mounted on a pair of glasses, a portable processor to translate the signal from the camera into electrical stimulation, and a microchip with electrodes implanted directly on the retina.

The study was authored by researchers at Second Sight, the company who developed the device, and has been published in Frontiers in Neuroprosthetics on the 22nd of November.

“In this clinical test with a single blind patient, we bypassed the camera that is the usual input for the implant and directly stimulated the retina. Instead of feeling the braille on the tips of his fingers, the patient could see the patterns we projected and then read individual letters in less than a second with up to 89% accuracy,” explains researcher Thomas Lauritzen, lead author of the paper.

Similar in concept to successful cochlear implants, the visual implant uses a grid of 60 electrodes — attached to the retina — to stimulate patterns directly onto the nerve cells. For this study, the researchers at Second Sight used a computer to stimulate six of these points on the grid to project the braille letters. A series of tests were conducted with single letters as well as words ranging in length from two letters up to four. The patient was shown each letter for half a second and had up to 80% accuracy for short words.

“There was no input except the electrode stimulation and the patient recognized the braille letters easily. This proves that the patient has good spatial resolution because he could easily distinguish between signals on different, individual electrodes.” says Lauritzen.

According to Silvestro Micera at EPFL’s Center for Neuroprosthetics and scientific reviewer for the article, “this study is a proof of concept that points to the importance of clinical experiments involving new neuroprosthetic devices to improve the technology and innovate adaptable solutions.”

Primarily for sufferers of the genetic disease Retinitis Pigmentosa (RP), the implant Argus II has been shown to restore limited reading capability of large conventional letters and short words when used with the camera. While reading should improve with future iterations of the Argus II, the current study shows how the Argus II could be adapted to provide an alternative and potentially faster method of text reading with the addition of letter recognition software. This ability to perform image processing in software prior to sending the signal to the implant is a unique advantage of Argus II.

Age-Related Macular Degeneration Treatment Works Even With Other Eye Problem, Study Finds

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Posted on 5th December 2012 by Pacific ClearVision Institute in General |Retina

The primary treatment for wet macular degeneration, a chronic eye condition that causes vision loss, is effective even if patients have macular traction problems, a Mayo Clinic study shows.

The findings will be presented today at the annual meeting of the American Academy of Ophthalmology in Chicago.

Due to the aging population, an increasing number of patients are being treated for age-related macular degeneration (AMD), an eye condition in which abnormal blood vessels develop and leak into the eye. When patients develop wet AMD, they receive injections of anti-vascular endothelial growth factor medication (VEGF). VEGF prompts growth of new blood vessels in the body. In the case of AMD, however, such new growth is unwanted and may cause bleeding in the retina.

It has not been clear whether this treatment would also serve patients experiencing other symptoms, such as vitreomacular interface disease (VMID), in which there is traction or contact between the retina and the vitreous matter in the eye. Mayo researchers retrospectively studied 178 patients, of whom 18 percent had VMID over an average of 2.5 years.

Findings showed that while eyes with some kind of macular traction required more injections, they still showed improvement (best corrected visual acuity) to similar eyes without VMID.

“This finding is significant,” says senior author Sophie J. Bakri, M.D., “because it showed that patients with VMID are not necessarily treatment resistant for AMD.” She also says it may help physicians not give up on treating such patients, and understand the need for more doses of medication for those with VMID. Researchers say more study is needed, including a prospective clinical trial.

Co-authors include Amy Green-Simms, M.D., Blake Fechtel and Zubin Agarwal, M.P.H., all of Mayo Clinic. The research was funded in part by Research to Prevent Blindness.

Immune System Could Play a Central Role in Age-Related Macular Degeneration

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Posted on 5th December 2012 by Pacific ClearVision Institute in General |Retina

Changes in how genes in the immune system function may result in age-related macular degeneration (AMD), the leading cause of visual impairment in older adults, based on preliminary research conducted by National Institutes of Health (NIH) investigators.

“Our findings are epigenetic in nature, meaning that the underlying DNA is normal but gene expression has been modified, likely by environmental factors, in an adverse way,” said Dr. Robert Nussenblatt, chief of the National Eye Institute (NEI) Laboratory of Immunology. Environmental factors associated with AMD include smoking, diet, and aging. “This is the first epigenetic study revealing the molecular mechanisms for any eye disease.”

The study identified decreased levels of DNA methylation, a chemical reaction that switches off genes, on the interleukin-17 receptor C gene (IL17RC). The lack of DNA methylation led to increased gene activity and, in turn, increased levels of IL17RC proteins in patients with AMD. IL17RC is a protein that promotes immune responses to infections, such as fungal attacks.

The study, conducted by research teams from the NEI and other NIH institutes, including the National Heart, Lung, and Blood Institute and the National Center for Complementary and Alternative Medicine; the University of Melbourne, Australia; and Oregon Health and Science University, appears in the Nov. 29 issue of Cell Reports.

“Our study also suggests IL17- and IL17RC-mediated immune responses can be crucial in causing AMD,” added Dr. Lai Wei, also of NEI’s Laboratory of Immunology and first author on the paper. “By measuring IL17RC gene activity in at-risk patients, we have also potentially identified an early method to detect AMD.”

AMD damages the light-sensitive cells of the macula, the central part of the retina that allows us to see fine visual detail. As the disease progresses, patients encounter great difficulty reading, driving, or performing hobbies and tasks that require hand-eye coordination. Treatments exist to prevent severe vision loss in certain types of advanced AMD but none prevent or cure the disease. Currently, 2 million Americans have advanced AMD and another 7 million have intermediate stages.

Recent studies have identified several genes with alterations that increase the risk of developing the disease. In addition, environmental risk factors have also been suggested as possible causes of the disease. One explanation may be that environmental exposures influence DNA methylation, which regulates gene expression. Changes in this process may result in the production of too much or too little of a gene’s protein, leading to cellular dysfunction and disease. Changes in DNA methylation have been implicated in cancer, lupus, multiple sclerosis, and many other diseases.

To test whether changes in DNA methylation might play a role in AMD, the investigators evaluated three pairs of twins — one pair identical and two pairs fraternal — where only one of the siblings had AMD. Identical twins have the same genetic makeup while fraternal twins share about half of their DNA. Because of their similar genetic backgrounds, identical and fraternal twins can be helpful in studying the differences between the effects of genetics and the environment. When compared with the unaffected twins, methylation patterns were altered in 231 genes of affected twins. This finding is consistent with the hypothesis that environmental exposures may epigenetically regulate expression of many genes and lead to AMD.

Among the 231 genes, the investigators found that DNA methylation was absent in a region of the IL17RC gene in twins with AMD. The lack of methylation in the IL17RC gene led to increased gene activity and, in turn, increased levels of its protein in circulating blood. The investigators further validated these findings by comparing seven siblings with and without AMD as well as 202 AMD patients and 96 control subjects without the disease. These studies also found increased IL17RC levels in circulating blood and, most importantly, in the retina of patients with AMD but not controls.

Based on these results, the authors propose that chronic increased levels of the IL17RC protein in the retina likely promote inflammation and recruitment of immune cells that damage the retina and lead to AMD.

“This study strongly implicates epigenetic DNA methylation as another crucial biological pathway for understanding the molecular basis of AMD,” according to Nussenblatt.

The investigators next plan to evaluate what environmental factors may be responsible for the regulation of IL17RC and how the epigenetic regulation leading to the chronic inflammation in AMD patients can be reversed by novel therapies. They will also evaluate the role of epigenetics in other eye diseases.

Engineering a Photo-Switch for Nerve Cells in the Eye and Brain

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Posted on 5th December 2012 by Pacific ClearVision Institute in General |Retina

Chemists and vision scientists at the University of Illinois at Chicago have designed a light-sensitive molecule that can stimulate a neural response in cells of the retina and brain — a possible first step to overcoming degenerative eye diseases like age-related macular degeneration, or to quieting epileptic seizures.

Their results are reported online in the journal Nature Communications.

Macular degeneration, the leading cause of vision loss in people over 50, is caused by loss of light-sensitive cells in the retina — the rods and cones.

“The rods and cones, which absorb light and initiate visual signals, are the broken link in the chain, even though what we call the ‘inner cells’ of the retina, in many cases, are still potentially capable of function,” says David Pepperberg, professor of ophthalmology and visual sciences in the UIC College of Medicine, the principal investigator on the study.

“Our approach is to bypass the lost rods and cones, by making the inner cells responsive to light.”

Pepperberg and his colleagues are trying to develop light-sensitive molecules that — when injected into the eye — can find their way to inner retinal cells, attach themselves, and initiate the signal that is sent to the brain.

The researchers synthesized new compounds built upon the well-known anesthetic agent propofol, a small molecule that binds to a receptor-protein on nerve cells. The receptor is ordinarily activated by the neurotransmitter GABA, and when so activated it opens a channel in the membrane of the cell to initiate a signal that propagates to other nerve cells.

Chemists led by Karol Bruzik, professor of medicinal chemistry and pharmacognosy in the UIC College of Pharmacy, succeeded in adding-on a light-sensitive chemical component to the propofol molecule. When struck by light of different wavelengths, the molecule changes shape and functions as a light-triggered, on-off switch for these receptors.

The research team tested the new compound, code name MPC088, in three different types of cells: retinal ganglion cells, the nerve cells that send visual signals from the retina to the brain via the optic nerve; Purkinje neurons from the cerebellum; and non-nerve cells that were specially engineered to produce and install the GABA receptor in their membrane.

MPC088 binds to the receptor and makes it far more responsive to GABA. Light of appropriate wavelengths converts the MPC088 to an inactive form and back again, reducing and then restoring the high sensitivity to GABA, which opens the membrane channel to initiate the neural signal.

“Putting it all together, we have a compound that dramatically regulates, in light-dependent fashion, the GABA receptors of both an engineered receptor system and native receptors of retinal ganglion cells and brain neurons,” Pepperberg said.

The experiments on the Purkinje neurons of the cerebellum, conducted in collaboration with neurobiologist Thomas Otis at the University of California at Los Angeles, “showed we were able to go beyond visual systems,” Pepperberg said, and demonstrate that “photo-regulation may also have potential as a therapeutic for epilepsy, a class of diseases that involves abnormal excitatory activity in the brain.”

Epileptic seizures begin in a defined region of the brain, and it may become possible to introduce a photo-switching compound and a very thin light-guide into this region, Pepperberg said.

“Because GABA receptors are typically inhibitory, introducing light of the appropriate wavelength into the region as the seizure begins and activating the GABA receptors could have the effect of turning off the seizure.”

The researchers also created a molecular switch related to MPC088 that can permanently anchor a genetically engineered GABA receptor, demonstrating the possibility that a light-sensitive molecule could be introduced into the eye or brain to modify GABA receptors and act as a photo-switch.

“Our work opens up new avenues for not only the retinal application but also diseases of the central nervous system where a dysfunction or deficiency of GABA activity is a key problem,” Pepperberg said.

Co-first authors on the paper were UIC bioengineering graduate student Lan Yue, UIC medicinal chemistry and pharmacognosy postdoctoral researcher Michal Pawlowski, and UCLA postdoctoral researcher Shlomo Dellal. Other authors were An Xie, Feng Feng, and Haohua Qian from the UIC department of ophthalmology and visual sciences.