Eyeblog November 2015

There have been plenty more fascinating articles for us this month.  We include further developments in the treatment of cataracts with simple eye drops.  Could this mean that surgery becomes a thing or the past or will this simply prove an excellent alternative for those that surgery is not an option?  And we are happy to hear that NICE have approved the use of ciclosporin for the treatment of severe keratitis. This will provide clinicians greater access to an excellent treatment options for those patients in whom lubricants have failed.

Please contact me with any questions you might have.

Rachel

Eye drops for cataracts a step closer with newly identified compound[i]

Researchers at the University of California-San Francisco (UCSF) recently published their findings in the journal Science.

Around 30% of the UK population aged 65 or older has a cataract in one or both eyes, with the incidence increasing exponentially with age[ii]

In the early stages, cataracts may be improved with magnifying lenses, new glasses, anti-glare sunglasses or brighter lighting. However, if such treatments fail, surgery is currently the only option.

Surgery for cataracts involves removing the cloudy lens and replacing it with an artificial one. However, Gestwicki and colleagues note that - although highly successful - cataract surgery is costly, and many people with cataracts in developing countries often go untreated as a result.

But in this latest study, the team demonstrates the possibility of a cheaper, more practical alternative to treating cataracts: eye drops containing a chemical that dissolves crystallins - proteins that clump together and cloud the lens.

Crystallins are arranged in the lens in a certain way that allows light to pass through it, enabling us to see. As we get older, however, these proteins can clump together, preventing light from being able to pass through the lens.

For their study, the team used a process called high-throughput differential scanning fluorimetry (HT-DSF) - a method in which proteins give off light when their melting point is reached - to apply heat to both healthy crystallins and their amyloid forms, while also applying various chemical compounds.

The researchers began testing 2,450 compounds, gradually narrowing them down to 12 that helped reduce the melting point of crystallin amyloids to the normal range. The 12 compounds identified were part of a class of chemicals called sterols.

The team identified one - referred to as "compound 29" - that they believed could be added to eye drops to help dissolve amyloid crystallins.

Gestwicki and colleagues then tested compound 29 on crystallin amyloids in a laboratory dish. They found the compound not only prevented clumps from forming, but it also successfully dissolved the clumps that had already formed.

Next, the researchers added compound 29 to eye drops and tested them in mice that possessed mutations that predisposed them to cataracts.

The team used a slit-lamp test to measure lens transparency in the mice and found the eye drops partially restored transparency to the lenses of mice with cataracts. What is more, on applying the eye drops to mice that developed age-related cataracts and cataract-affected human lens tissue that had been removed through surgery, they saw similar results.

The team stresses that the slit-lamp test does measure visual awareness, and as such, clinical trials are needed to determine whether compound 29 can improve vision in humans with cataracts.

The compound has already been licensed, and study co-leader Leah N. Makley, is in the process of formulating the compound so it is ready for human use.

If compound 29 is found to be a success, it may not only lead to new treatments for cataracts; it could also open the door to new treatments for other conditions involving amyloid proteins, such as Alzheimer's disease.

NICE recommends the use of IKERVIS® in England for the treatment of severe keratitis in adult patients with dry eye disease[iii]

NICE issues positive Final Appraisal Determination (FAD) recommending the use of Santen's IKERVIS® (ciclosporin 1 mg/mL eye drops emulsion in single-dose containers) for the treatment of severe keratitis in adult patients with dry eye disease, which has not improved despite treatment with tear substitutes.

IKERVIS® is the first and only topical ciclosporin preparation licensed for the treatment of severe keratitis in patients with dry eye disease in the UK. Approximately 700,000 adults in Europe suffer from the severe form of dry eye disease. Symptoms of dry eye disease include burning, itching and dryness, gritty sensation and photophobia.  Severe keratitis is an inflammation of the cornea, which can result from dry eye disease.

Patients may present with signs of serious ocular surface damage but their symptoms may not correlate to the clinical signs, making diagnosis difficult. However, inflammation if left untreated can lead to further complications, permanent corneal damage and even loss of sight.

Professor Figueiredo, Professor of Ophthalmology at Newcastle's Royal Victoria Infirmary and Newcastle University, said, "NICE's positive appraisal of Ikervis means that UK patients with severe keratitis and dry eye disease will have access for the first time to a licensed product with the potential to have a significant positive impact. Patients with this particularly unpleasant and disabling condition have a seriously impaired quality of life, and patients often have been unable to access licensed treatment that they need. Ophthalmologists now have a new and licensed treatment option that could make a real difference to our patients"

Ciclosporin works by reducing inflammation in dry eye disease.  However, until the launch of IKERVIS®, there has been no topical preparation of ciclosporin licensed in the UK.  With this recommendation from NICE, IKERVIS® provides an important new option for the treatment of patients in England who have not responded to tear substitutes.

The NICE decision was based on data from the SANSIKA trial. This was a double-masked multicentre, randomised, vehicle-controlled six month pivotal phase III trial with a six month open label treatment safety follow up period, which evaluated the efficacy and safety of IKERVIS®, administered once daily in adult patients with severe dry eye disease. Key evidence from SANSIKA showed that IKERVIS® with once-daily dosing, reduces ocular surface inflammation and reduces corneal damage, and is consistent with an improvement in patients' disease severity.

Mr Craig Wallace, General Manager for Santen UK and Ireland said, "This recommendation by the globally renowned NICE institute underscores what an important medicine Ikervis® is for patients with severe dry eye diseases. This is a very proud moment for Santen."



[i] H Whiteman, “Eye drops for cataracts a step closer with newly identified compound”, 6th November 2015, Medical News Today. Retrieved from http://www.medicalnewstoday.com/articles/302121.php. Last accessed on 9th November 2015

[ii] Royal College of Ophthalmology, Cataract Surgery Guidelines, 2010

[iii] “NICE recommends the use of IKERVIS® in England for the treatment of severe keratitis in adult patients with dry eye disease”, 6th November 2015, Medical News Today. Retrieved from http://www.medicalnewstoday.com/releases/302214.php . Lat accessed on 9th November 2015.

October 2015

We’re back with more exciting updates about current research in Ophthalmology.

We may be one step closer to a cure for age related macular degeneration! Surgeons in London have carried out the first stem cell transplant for AMD as part of an 18 month trial.

Does the new research carried out in dogs hold the key to colour blindness? A study has shown that gene therapy may be the answer.

Look out for more news in the coming months.

Rachel

 

Age-related blindness cure steps closer with new stem cell trial

Surgeons in the UK have successfully transplanted eye cells derived from stem cells behind the retina of a patient with wet age-related macular degeneration. The operation is the first to be performed in the London Project to Cure Blindness, a UK-based collaboration aiming to cure vision loss in patients with this disease.

Age-related macular degeneration (AMD) is a leading cause of vision loss among people aged 50 and older, while macular degeneration in general accounts for nearly half of all visual impairment in the developed world. There are two types of AMD. The most common type is dry AMD, accounting for around 90% of macular degeneration cases. It is caused by the degeneration of the layer of retinal pigment epithelial (RPE) cells in the macula. Less common and more severe is wet AMD, typically caused by abnormal blood vessels leaking fluid or blood into the macula region. Cases of wet AMD usually begin as dry AMD.

The London Project to Cure Blindness is examining whether transplanting RPE cells can be a safe and effective form of treatment for wet AMD. For the trial, RPE cells derived from stem cells are used to replace those damaged by wet AMD via a special patch that is surgically inserted behind the retina.

Prof. Da Cruz carried out the first of these transplants on a patient last month and, so far, no complications have been reported. We will have to wait until Christmas though to know whether the transplant has had any affect upon the patient’s vision. In full, the trial will assess 10 patients with wet AMD over the course of 18 months. After receiving the transplanted RPE cells, each patient will be observed for a year so that the safety and efficacy of the treatment can be monitored

If this new form of treatment is found to be successful, the researchers believe that it could also be used to help patients whose vision is being eroded by the early stages of dry AMD; it may also lead to treatments for other eye conditions too.

References:

“Age-related blindness cure steps closer with new stem cell trial”, Sept 29, 2015, Medical News Today. Retrieved from http://www.medicalnewstoday.com/articles/300201.php. Accessed October 05, 2015

 

Cure for rare form of color blindness steps closer with novel gene insight

Achromatopsia is an inherited disorder that affects around 1 in 30,000 people. The condition is triggered by abnormalities in the retina. People with achromatopsia will experience partial or total loss of color vision, as well as sensitivity to light.

At present, there is no cure for achromatopsia. Current treatments to help manage the condition include the use of red-colored lenses to reduce sensitivity to light and boost visual functioning.

However, ongoing research using animal models has identified gene therapy as a promising avenue for an achromatopsia cure, and this latest study - conducted by researchers from Temple University in Philadelphia, PA, and the University of Pennsylvania - brings the strategy one step closer.

Senior author Karina Guziewicz, of the School of Veterinary Medicine at the University of Pennsylvania, and colleagues began their study by analyzing a German shepherd dog who display classical symptoms of achromotopsia. The researchers set out to identify the genetic cause of the dog's vision loss, though they found none of the known gene mutations that lead to achromatopsia in dogs.

By analyzing five genetic mutations known to play a part in how light signals are sent from the eye to the brain. The team identified a mutation in a gene called CNGA3 that was responsible for the German shepherd's vision loss.

On analyzing Labrador retrievers that had similar symptoms of vision loss to the German shepherd, the researchers identified a different mutation on the same area of the CNGA3 gene where the German shepherd's mutation was found.

The team notes that these mutations have never before been identified in dogs, but the gene mutation found in the German shepherd have been found in humans, highlighting dogs as a valuable model in which to study human achromatopsia.

Next, the team adopted a supercomputer technique that allowed them to identify small changes in protein sequences that may have important implications for visual signaling.

From this, they found that the two mutations found in the CNGA3 gene of dogs impaired the function of the cyclic nucleotide channel, which plays a major role in converting visual signals.

These findings, the researchers say, offer new insights into the molecular mechanisms underlying achromatopsia and emphasize the potential for gene therapy to cure the condition in both dogs and humans.

 

References:

H Whiteman, “Cure for rare form of color blindness steps closer with novel gene insight”, October 05, 2015, Medical News Today. Retrieved from http://www.medicalnewstoday.com/articles/300426.php. Accessed on October 05, 2015

October 2014

Some exciting results from trails looking at embryonic stem cells in treating blindness! The future in this fascinating area looks bright. A basic science paper explains a new mechanism involved in photoreceptor cell death. And lastly may reading glasses be a thing of the past? Corneal inlays show some promising results.

 

Enjoy!

 

Ellie

 

How safe are human embryonic stem cell transplants?

 

Evidence of the medium- to long-term safety of transplanting human embryonic stem cells has been published for the first time, in a report in The Lancet.

 

Since 1981, when pluripotential cell cultures were first derived, human embryonic stem cells (hESCs) have been considered to be a potential source of cells to treat diseases caused by tissue loss or dysfunction. However, scientists were concerned that the self-renewing abilities of these cells could lead to problems such as tumor development. Despite plenty of animal studies over the past 3 decades, there have been no assessments of the long-term safety or effectiveness of hESCs in humans.

Embryonic stem cells have the potential to become any cell type in the body, but transplantation has been complicated by problems including the risk of teratoma formation and immune rejection. As a result, immunoprivileged sites (that do not produce a strong immune response) such as the eye have become the first parts of the human body to benefit from this technology.

Across two studies, hESCs were transplanted into 18 patients with severe vision loss. Nine of the patients had atrophic age-related macular degeneration and nine had Stargardt macular dystrophy - these conditions eventually cause complete blindness and there are no effective treatments for them. The participants were injected with a dose of either 50,000, 100,000, or 150,000 retinal cells under the retina in their eye that had the worst vision. The authors found that the hESC-derived cells were well tolerated for up to 37 months after transplantation. During a median follow-up of 22 months, no safety concerns were found. Some adverse events were associated with surgery and immunosuppression, but the authors state that these events were not related to the hESC-derived cells.

Follow-up testing in the first year after transplant demonstrated that eight of the patients were now able to read over 15 additional letters. In seven patients, visual acuity remained the same or improved. One patient, however, reported a decrease in visual acuity by more than 10 letters.

 

References:

Steven D Schwartz, et al. Human embryonic stem cell-derived retinal pigment epithelium in patients with age-related macular degeneration and Stargardt’s macular dystrophy: follow-up of two open-label phase 1/2 studies,., The Lancet, http://dx.doi.org/10.1016/ S0140-6736(14)61820-1, published online 15 October 2014.

McNamee, D. (2014, October 15). "How safe are human embryonic stem cell transplants?." Medical News Today. Retrieved from
http://www.medicalnewstoday.com/articles/283913.php. Accessed October 20th 2014.

Discovery of a new mechanism that can lead to blindness

It has been discovered that a protein found in the retina plays an essential role in the function and survival of light-sensing cells that are required for vision. These findings could have a significant impact on our understanding of retinal degenerative diseases that cause blindness.

A process called compartmentalization was studied, which establishes and maintains different compartments within a cell, each containing a specific set of proteins. This process is crucial for neurons (nerve cells) to function properly. Compartments within a cell are much like different parts of a car, in the same way that gas must be in the fuel tank in order to power the car's engine, proteins need to be in a specific compartment to properly exercise their functions. A good example of compartmentalization is observed in a specialized type of light-sensing neurons found in the retina, the photoreceptors, which are made up of different compartments containing specific proteins essential for vision.

The authors identified a new mechanism that explains how compartmentalization is achieved within photoreceptor cells. More specifically, a protein called Numb was found to function like a traffic controller to direct proteins to the appropriate compartments. In the absence of Numb, photoreceptors are unable to send a molecule essential for vision to the correct compartment, which causes the cells to progressively degenerate and ultimately die.

This is important because the death of photoreceptor cells is known to cause retinal degenerative diseases in humans that lead to blindness. This work therefore provides a new piece of the puzzle to help us better understand how and why the cells die. This could eventually have a substantial impact on the development of treatments for retinal degenerative diseases, like retinitis pigmentosa and Leber's congenital amaurosis, by providing novel drug targets to prevent photoreceptor degeneration.

References:

Ramamurthy et al. Numb Regulates the Polarized Delivery of Cyclic Nucleotide-Gated Ion Channels in Rod Photoreceptor Cilia The Journal of Neuroscience. 2014, 34(42): 13976-13987

IRCM. (2014, October 17). "Discovery of a new mechanism that can lead to blindness." Medical News Today. Retrieved from
http://www.medicalnewstoday.com/releases/284021.php.
 Accessed 20th October

 

Corneal inlays may remove need for reading glasses

Implantable eye devices called corneal inlays are designed to correct presbyopia - the age-related loss of near vision that affects over a billion people worldwide. Delegates at a recent scientific meeting learned how one such device - the KAMRA inlay - improved near vision well enough for 80% of study participants to be able to read a newspaper without impairing far distance vision for common activities such as driving.

Currently, there are three designs of corneal inlays, each varying in size, material and mechanism of action.

Generally, corneal inlays have complications such as haziness that can be treated with steroids, but newer designs are managing to minimize these. If necessary, corneal inlays can be removed, making the treatment reversible, unlike other procedures such as LASIK laser eye surgery for presbyopia.

John Vukich, a clinical adjunct professor in ophthalmology and vision sciences at the University of Wisconsin, Madison, presented the results of a study on the efficacy of the KAMRA corneal inlay at AAO 2014, the 118th annual meeting of the American Academy of Ophthalmology, that is running from October 17th to 21st in Chicago, IL.

Prof. Vukich says corneal inlays are "a great opportunity to improve vision with a safety net of removability," and the study results show the KAMRA inlay is "a solution that truly delivers near vision that transitions smoothly to far distance vision."

The KAMRA inlay is a thin, flexible ring with a diameter of 3.8 mm and a hole measuring 1.6 mm in the middle. Once implanted in the cornea - the clear tissue covering the front of the eye - it acts like a camera aperture, adjusting the depth of field to enable near and far vision. It takes about 10 minutes to implant the inlay, and the patient only needs a local anesthetic to numb the surface of the eye.

A prospective non-randomized study of the KAMRA inlay was carried out in 507 non-nearsighted patients with presbyopia aged between 45 and 60 who attended clinics in different parts of the US, Europe and Asia. After implanting the devices, they followed the patients for 3 years. Authors found that in 83% of the presbyopic patients, the corneal implant allowed them to see with 20/40 vision or better over the follow-up period. This is considered the standard for being able to read newsprint or drive a vehicle without requiring glasses. On average, the participants gained 2.9 lines on a reading chart, and the results remained steady over the follow-up.

The KAMRA inlay is already available for commercial use in Asia, Europe and South America. I

Two other types of corneal inlays - the Raindrop Near Vision Inlay that works by changing the shape of the cornea and the Presbia Flexivue Microlens that changes the refractive index of the cornea - are also in development for the US market.

References:

Treating emmetropic presbyopes with a small aperture inlay: three year results, presented by John Vukich, at AAO 2014, 118th annual meeting of the American Academy of Ophthalmology, October 17 -21, Chicago.

Paddock, C. (2014, October 20). "Corneal inlays may remove need for reading glasses." Medical News Today. Retrieved from
http://www.medicalnewstoday.com/articles/284095.php. Accessed 27th October 2014.

 

 

September 2014

 

September  has  been a busy month in the world of research. You may notice that my blog has a slight genetics slant, this is due to my background in genetics research and my belief  that it underpins the future of tailor made therapies. The genetics studies described lead us one step closer to a cure/prevention for glaucoma. Before reading the dry eye article I was unaware just how prevalent it is! Very interesting that it is associated  to long term pain syndromes also. I think we are all relieved to see that Cochrane has released a review regarding the Avastin and Lucentis debate – the amount the NHS could save by using  Avastin is astronomical. Lastly the association of exfoliation syndrome and being outdoors raises many questions about the role UV light plays in the pathogenesis of this disease. I hope you enjoy reading about these studies as much as I did and remember, if you want to contact me I’d love to hear from you!

Ellie

This email address is being protected from spambots. You need JavaScript enabled to view it.">This email address is being protected from spambots. You need JavaScript enabled to view it. 

ABCA1 variants linked to glaucoma risk

The identification of ABCA1 variants associated with risk of developing glaucoma is reported in three independent studies published online this September in Nature Genetics. These findings may lead to better diagnostic tools or therapies for glaucoma.

Glaucoma is a group of eye disorders that cause progressive damage to the optic nerve and can lead to permanent blindness. Though high intraocular pressure is a common risk factor for developing glaucoma, people with normal eye pressure can also develop the disease.

One study found variants near the two genes ABCA1 and PMM2, which are associated with glaucoma risk, with or without high intraocular pressure, in individuals from China and Singapore1. Both genes have been previously implicated in other eye disorders, but not glaucoma. In a second study, variants near three genes, including ABCA1, were found to be associated with glaucoma risk in Australians and Americans of European descent2. The third study combines genetic data from 18 populations, including people of Asian and European descent, and also identifies ABCA1 as a risk gene for both high intraocular pressure and glaucoma3.

ABCA1 is a major regulator of cellular cholesterol and lipid levels. Previous studies have found that this gene is expressed at higher than normal levels in the blood of glaucoma patients, and therefore this may represent a promising drug target.

 

References:

 1.Yuhong Chen et al. Common variants near ABCA1 and in PMM2 are associated with primary open-angle glaucoma. Nature Genetics doi:10.1038/ng.3078

 

2.Pirro G Hysi et al. Genome-wide analysis of multi-ancestry cohorts identifies new loci influencing intraocular pressure and susceptibility to glaucoma. Nature Genetics doi:10.1038/ng.3087

 

3.Puya Gharahkhani et al. Common variants near ABCA1, AFAP1 and GMDS confer risk of primary open-angle glaucoma. Nature Genetics doi:10.1038/ng.3079

 

 

Around 1 in 10 UK women has dry eye disease, requiring artificial tears

 

Around one in 10 women in the UK has dry eye disease, requiring artificial tears or gel to lubricate the eyes and protect them from damage, reveals a study published online in the British Journal of Ophthalmology.

Altered pain perception and psychological factors may be involved in the condition, the researchers report.

The symptoms of dry eye disease include the sensation of grit in the eye, frequently accompanied by itching, burning and visual disturbance. The causes are poorly understood.

The participants consisted of almost 4000 women aged 20 to 87 (average age 57) from the TwinsUK cohort, drawn from the registry held at St Thomas' Hospital in London. This cohort is widely regarded as representative of the UK general population, and has been used to look at a wide range of diseases and genetic traits over the years.

The prevalence of dry eye disease, and the frequency and severity of symptoms, were assessed through questionnaires mailed out to the women. At the same time 681 randomly selected twins from the cohort, who were taking part in a subsidiary study on pain, supplied additional information on dry eye symptoms and rated their own health on a five point scale.

Around one in 10 of the women (9.6%) had been diagnosed with dry eye disease, which was being treated with artificial tear eye drops or gel. One in five (just under 21%) had experienced symptoms in the past three months.

The analysis showed that the prevalence of a diagnosis of dry eye disease rose with age, from 2.7% among women in their 30s to one in five of those in their 90s.

Cataract surgery, age related macular degeneration, and glaucoma were all significantly associated with dry eye disease, as was the use of contact lenses. Autoimmune diseases, such as thyroid problems, rheumatoid arthritis, and allergies asthma and eczema were also linked to a heightened risk. Furthermore, fertility problems were strongly associated with dry eye disease, as was osteoarthritis.

The strongest associations were found with long-term pain syndromes (known as chronic pain syndromes), such as irritable bowel syndrome, pelvic pain, and chronic widespread pain syndrome (also known as fibromyalgia). People with these conditions also tended to have depression and migraine - risk factors for dry eye disease in their own right.

The responses to the health questionnaire showed that people with dry eye symptoms rated their health, on average, worse than those without symptoms. They highlighted difficulties watching TV, driving, working online, and experienced discomfort in places that were air conditioned or where the air was dry.

The authors conclude that dry eye disease is very common among women and that it has a significant impact on perceived quality of life. They add that their findings suggest that altered pain perception as well as psychological factors may influence the development of the condition and symptom severity, and that some patients might be helped by treating the pain rather than just lubricating the eyes.

 

References:

 

Jelle Vehof, Diana Kozareva, Pirro G Hysi, Christopher J Hammond. Prevalence and risk factors of dry eye disease in a British female cohort. British Journal of Ophthalmology, doi:10.1136/bjophthalmol-2014-305201, published 3 September 2014.

 

 

Cheaper alternative to licensed drug for treating age related macular degernaeration has similar side-effects says new Cochrane Review

 

Health policies which favour using ranibizumab for treating eye disease in older people over safety concerns for a cheaper alternative should take account of a new Cochrane Review. The researchers looked at the results of studies which compared the safety of two drugs used for treating age-related macular degeneration, ranibizumab and bevacizumab. Contrary to what was argued by some experts the review has found that the cheaper drug, bevacizumab, does not appear to increase deaths or serious side-effects compared with ranibizumab in people with neovascular age-related macular degeneration.

Neovascular macular degeneration is a progressive and chronic disease of the eye, and a leading cause of blindness in older people. About one in 10 people with macular degeneration suffers legal blindness. Bevacizumab is a drug that has been developed to treat cancer, while ranibizumab is marketed specifically for age-related macular degeneration. The two drugs are better known by their brand names Avastin (bevacizumab) and Lucentis (ranibizumab). The authors conclude that health policies that favour the much more costly ranibizumab instead of bevacizumab for macular degeneration, for reasons of safety, are not supported by current randomised controlled trial evidence. A larger Cochrane Review, which will assess additional sources of evidence, is now planned to help reduce the remaining uncertainties around the relative benefits and safety of these drugs.

Bevacizumab and ranibizumab are related biological drugs that work to prevent the abnormal growth and swelling of blood vessels that are characteristic signs of macular degeneration. Although the beneficial effects of the two drugs are believed to be similar, only ranibizumab has been licensed as a treatment for macular degeneration; bevacizumab is currently approved only as a cancer therapy. Despite this, an unlicensed preparation of bevacizumab is often used off-label as treatment for macular degeneration, because it is cheaper than ranibizumab. It has been suggested that the two drugs have different safety profiles, such that bevacizumab might cause more systemic harms, and the review investigated this concern.

The review included nine randomised controlled trials (RCTs), three of which had not been published. None of the trails were supported by manufacturers of either treatment, and a total of 3665 participants were used. The drugs were given for up to two years. The review found the systemic safety of bevacizumab for macular degeneration appeared to be similar to that of ranibizumab, except for gastrointestinal disorders. Although no statistically significant differences between the treatments were found, the review does not exclude the possibility that either treatment is less harmful than the other. The researchers estimated that if 1000 people were treated with ranibizumab for one to two years, 34 would die; if treated instead with bevacizumab, between 27 and 53 would die. If 1000 people were treated with ranibizumab, 222 would experience one or more serious systemic adverse events. If 1000 people were treated instead with bevacizumab, between 200 and 291 would experience such an event.

They rated the overall quality of the evidence as low to moderate because of the uncertainty of the findings, and due to other study limitations. Additionally, the review authors indicated that they could not fully assess the quality of three of the studies as they had not yet been published.

 

References:

 

Moja L, Lucenteforte E, Kwag KH, Bertele V, Campomori A, Chakravarthy U, D'Amico R, Dickersin K, Kodjikian L, Lindsley K, Loke Y, Maguire M, Martin DF, Mugelli A, Mühlbauer B, Püntmann I, Reeves B, Rogers C, Schmucker C, Subramanian ML, Virgili G., Systemic safety of bevacizumab versus ranibizumab for neovascular age-related macular degeneration, Cochrane Database of Systematic Reviews 2014, Issue 9. Art. No.: CD011230. DOI: 10.1002/14651858.CD011230.pub2, published 15 September 2014.

 

Outdoor activities may be linked to exfoliation syndrome in eyes

 

Outdoor activities may increase the odds of developing exfoliation syndrome (XFS) in the eyes, a condition which has been linked to cataracts and glaucoma.

XFS is a harmful aging of the eye associated cataracts, elevated intraocular pressure and retinal vein blockage. There is evidence that climate factors contribute to XFS. For example, aboriginal Australians who spend lots of time outdoors have a higher prevalence of the disorder. The relationship between ultraviolet (UV) radiation (UVR) and XFS however requires further study because reports of a link have not been consistent.

The authors examined the relationship between UVR and XFS in a study with clinic participants in the United States (118 cases, 106 control patients) and Israel (67 cases, 72 control participants). The authors analyzed the latitude where people lived and the average number of hours per week that they spend outside.

Where people live appears linked to XFS, with each degree of weighted lifetime average residential latitude away from the equator associated with an 11 percent increased odds of XFS. Every hour per week spent outside during the summer, averaged over a lifetime, also was associated with a 4 percent increased odds of XFS. The odds of XFS decreased by 2 percent in the United States, but not in Israel, for every 1 percent of average lifetime summer time during the day that sunglasses are worn. In the United States, a history of working over water or snow also was associated with increased odds of XFS. There appeared to be no association between brimmed hat wear and XFS.

This study provides evidence for a role of reflected UV rays in contributing to XFS. It by no means excludes other genetic and environmental mechanisms in XFS pathogenesis. If confirmed in other studies, there could be reason to consider more widespread use of UV-blocking eyewear in the prevention of XFS.

 

References:

 

JAMA Ophthalmol. Published online September 4th 2014. doi:10.1001/.jamaopthalmol.2014.3326. accessed September 20th 2014

August 2014

August brings some basic science, genetics and optometry research to the eye blog. If you have any comments of suggestions please do contact me, I would love to hear from you.

 

Elewys Hearne

This email address is being protected from spambots. You need JavaScript enabled to view it.

 

Cholecystokinin octapeptide antagonizes apoptosis in retinal pigment epithelial cells

 

Oxidative stress can cause retinal pigment epithelial (RPE) cell apoptosis. Nitric oxide and superoxide react to produce peroxynitrite, which, along with its derivatives, are strong oxidants. Cholecystokinin octapeptide-8 (CCK-8) can protect cholinergic neurons against basal forebrain lesions caused by brain injury.

Dr. Yuan Liu research team in China treated human RPE cells with the oxidative stress inducer peroxynitrite, and evaluated the neuroprotective effects of CCK-8. Peroxynitrite triggered apoptosis in these cells, and increased the expression of Fas-associated death domain, Bax, caspa-se-8 and Bcl-2.

These changes were suppressed by treatment with CCK-8. These results suggest that cholecystokinin octapeptide-8 can protect human retinal pigment epithelial cells against apoptosis induced by peroxynitrite.

References:

 

Liu Y, Zhang YL, Gu ZH, Hao LN, Du J, Yang Q, Li SP, Wang LY, Gong SL. Cholecystokinin octapeptide antagonizes apoptosis in human retinal pigment epithelial cells. Neural Regen Res. 2014;9(14):1402-1408.

 

Inhibiting FGF pathways in the eye may help patients with age-related macular degeneration or diabetic retinopathy

 

Mice missing two important receptor proteins of the vascular system (FGFR1 and FGFR2) develop normally and appear healthy in adulthood, as long as they don't become injured. If they do become injured, their wounds don't heal properly. This may have implications for treating diseases involving abnormal blood vessel growth, such as the impaired wound healing often seen in diabetes mellitus and the loss of vision caused by macular degeneration.

FGF proteins are signaling molecules that play broad roles in embryonic development, tissue maintenance, and wound healing. They interact with specific receptor molecules, FGF receptors (FGFRs), located on the surface of many types of cells in the body.

When an organ is injured, the healing process involves the growth of new blood vessels. Since the cells lining the interior of blood vessels and blood cells themselves are important for developing new vasculature, the authors asked what would happen if they turned off signaling of the FGFR1 and FGFR2 proteins, two major mediators of the FGF signal that are present in the cells that line blood vessels. Their strategy differed from past studies, which shut down this signaling more broadly.

 The mutant mice appeared normal; running around and lived to an average age. Genetic tests were performed to confirm the mutant mice actually lacked these proteins, which they did. When the authors challenged these mice, they saw that they healed from a skin injury more slowly than their normal littermates, and that the density of blood vessels surrounding the injury site was significantly decreased.

The investigators also looked at the eyes. Like any other organ, new blood vessels grow in the eye in response to disease or injury. However, unlike the rest of the body, new blood vessels are not desired here, since they bleed, cause scar tissue formation and block light to the retina, causing vision loss.

The paper suggests that increasing FGF signaling in the body might help improve wound healing by increasing new blood vessel growth following an injury. This particularly applies to those who have trouble healing, such as patients with diabetes-related foot ulcers. Human FGF2 is already in clinical use as a topical spray in Japan for foot ulcers and similar wound healing purposes.

Conversely, inhibiting these pathways in the eye might help patients with age-related macular degeneration or diabetic retinopathy. Such patients grow new blood vessels in response to these diseased or injured states, but the new vessels only serve to obscure vision, not help heal an abnormal eye. As this research suggests these FGF pathways are not involved with normal development and tissue maintenance, any treatments boosting or inhibiting these signals would likely not effect healthy tissue.

 

References:

 

Oladipupo S, Smith C, Santeford A, Park C, Sene A, Wiley LA, Osei-Owusu P, Hsu J, Zapata N, Liu F, Nakamura R, Lavine KJ, Blumer KJ, Choi K, Apte RS, Ornitz DM. Endothelial cell FGF signaling is required for injury response but not for vascular homeostasis. PNAS Early Edition. Aug. 18, 2014.

 

http://www.medicalnewstoday.com/releases/281263.php accessed August 26th 2014

 

 

DNA test for congenital cataracts leads to faster, more accurate diagnoses of rare diseases linked to childhood blindness

 

Researchers in the United Kingdom have demonstrated that advanced DNA testing for congenital cataracts can quickly and accurately diagnose a number of rare diseases marked by childhood blindness, according to a study published online in Ophthalmology, the journal of the American Academy of Ophthalmology. Using a single test, doctors were able to tailor care specifically to a child's condition based on their mutations reducing the time and money spent on diagnosis and enabling earlier treatment and genetic counseling.

Each year, between 20,000 and 40,000 children worldwide are born with congenital cataracts, a disease that clouds the lens of the eye and often requires surgery and treatment to prevent blindness(1). The disease can arise following a maternal infection or be inherited as an isolated abnormality. Congenital cataracts can also appear as a symptom of more than 100 rare diseases, making mutations in the 115 genes associated with congenital cataracts useful as diagnostic markers for the illnesses.

Diagnosing these rare diseases previously proved a lengthy, costly and inconclusive process involving numerous clinical assessments and taking a detailed family history. DNA testing, one gene at a time, would have taken years to complete. Employing new DNA sequencing technology, called targeted next-generation sequencing, researchers at the University of Manchester sped up diagnosis to a matter of weeks by testing for mutations in all 115 known congenital cataracts genes at one time.

In 75 percent of the 36 cases tested, the DNA test determined the exact genetic cause of congenital cataracts. In one case, the DNA test helped diagnose a patient with Warburg Micro syndrome, an extremely rare disease that is marked by an abnormally small head and the development of severe epilepsy, among other medical issues. Having a clear diagnosis allowed for genetic counseling and appropriate care to be delivered quicker than previously possible without the test. The researchers also found previously undescribed mutations linked to cataract formation.

The test was made available to U.K. patients through the country's National Health Service in December 2013. Infants and children who have congenital cataracts can be tested as well as prospective parents with a history of the condition who wish to evaluate the risk to their child. Results generally take about two months. While only available in the U.K., the congenital cataract DNA test can be requested by registered medical facilities through international referral.

As with all genetic testing, the American Academy of Ophthalmology encourages clinicians and patients to consider the benefits as well as the risks. Ophthalmologists who order genetic tests either should provide genetic counseling to their patients themselves, if qualified to do so, or should ensure that counseling is provided by a trained individual, such as a board-certified medical geneticist or genetic counselor.

 

References

(1) Epidemiology of cataract in childhood: a global perspective, J Cataract Refract Surg. 1997;23 Suppl 1:601-4.

Personalized Diagnosis and Management of Congenital Cataract by Next-Generation Sequencing, Rachel L. Gillespie, MSc, James O’Sullivan, BSc, Jane Ashworth, FRCOphth, SanjeevBhaskar, MSc, Simon Williams, PhD, SusmitoBiswas, FRCOphth, Elias Kehdi, FRANZCO, Simon C. Ramsden, FRCPath, Jill Clayton-Smith, FRCP, Graeme C. Black, DPhil, FRCOphth, I. Christopher Lloyd, FRCOphth, Ophthalmology, DOI: 10.1016/j.ophtha.2014.06.006, published online 19 August 2014.

http://www.medicalnewstoday.com/releases/281442.php accessed 26th August 2014

Increased macular pigment may improve outdoor vision

Individuals with greater amounts of yellow pigment in the eye may be better able to see distant objects in hazy conditions. Increased macular pigment (MP) may help in filtering out "blue haze," thus making distant objects more visible.

The researchers tested the effects of MP on the ability to see distant objects through "atmospheric scattering," or haze. "All human eyes, and many animal eyes, contain an inert yellow pigment that is reported to be both protective and also slightly enhance vision, particularly in short wavelength (blue light) settings," Dr Adams explains. Some people have more MP than others.

The researchers designed an experiment to simulate hazy conditions to see if individuals with higher levels of MP can better see distant targets. Laboratory studies were performed using xenon light, paired with a specialized glass filter, to closely approximate the effects of atmospheric haze. The subjects varied widely in the density of MP present in the eye.

At increasing levels of simulated blue haze background, the visibility of distant objects decreased significantly. However, individuals with higher levels of MP required more stimulated haze before they could no longer see the distant target.

For subjects with the highest versus lowest levels of MP, there was about a twofold difference in the amount of haze required to lose sight of the distant object. The researchers write, "An individual with high MP optical density would be able to detect a target at a much greater distance (ie, more atmospheric haze between them and the target) than an individual with lower MP optical density."

The presence of yellow pigment in the macula represents accumulations of the nutrients lutein and zeaxanthin. By filtering out short-wave light, MP may protect long-term damage to the eye.

But from an evolutionary standpoint, it's much more likely that accumulations of MP could develop as a result of favorable effects on vision. The new findings support the "visibility hypothesis" of MP accumulation: by absorbing atmospheric haze, which is predominantly short-wavelength light, the presence of MP may extend visual range outdoors.

In this experiment, the effect seems large enough to provide a visual advantage of higher levels of MP for people who rely heavily on outdoor vision - for example, pilots. According to the authors, the next step in research would be to test the effects of different levels of MP on visibility in outdoor settings.

 References:

Visibility through Atmospheric Haze and Its Relation to Macular Pigment. Optometry & Vision Science: September 2014 - Volume 91 - Issue 9 - p 1089-1096 

July 2014

Hello and welcome to the eye research blog! I will give you a monthly update on the latest Ophthalmology research articles which I feel any medical professional interested in Ophthalmology will find useful and interesting. Enjoy!

Elewys Hearne

1. Early Age related Macular Degeneration can be seen in 35 – 44 year olds

In order to identify the age and gender specific incidence of Age related Macular Degeneration (AMD), the research team of the Department of Ophthalmology at the Mainz University Medical Center assessed the status of the ocular fundus of 4,340 participants in the Gutenberg Health Study. Vascular structure was assessed along with the head of the optic nerve, and the macula. The results unsurprisingly found that the incidence of AMD increases with age. The researchers also discovered that participants under the age of 50 years can already show signs of early stage AMD. In the age group of 35 - 44 year olds, 3.8 percent of the subjects were found to be suffering from the disease. These findings thus contradict the current assumption that age-related macular degeneration only occurs in the section of the population that is over 50 years old.

With the help of their findings, the researchers were also able to gain insights into how frequently the various forms of age-related macular degeneration occur. On average, about 12 percent of the examined 35 – 74 year olds had early stage AMD, but only 0.2 percent of the study participants exhibited symptoms of late stage AMD, which is often associated with severe visual impairment.

This research shows that age-related macular degeneration can occur much earlier than previously thought. This means there may also be possible consequences with regard to the screening examinations for these diseases.

References:

Korb CAKottler UBWolfram CHoehn RSchulz AZwiener IWild PSPfeiffer NMirshahi A. Prevalence of age-related macular degeneration in a large European cohort: Results from the population-based Gutenberg Health Study. Graefes Arch Clin Exp Ophthalmol. 2014 Feb 25. [Epub ahead of print]

http://www.uni-mainz.de/presse/17502_ENG_HTML.php accessed 30 July 2014

2. Human corneal tissue grown in mice using adult-derived human stem cells

Limbal stem cells replenish corneal cells as they become damaged. Injury or disease can lead to loss of these stem cells, and the eye loses its ability to keep the cornea transparent, resulting in significant loss of vision and eventually, blindness.

The only treatment option for patients who have lost their limbal stem cells is transplantation. This is complicated by the fact limbal stem cells are not easy to identify, so Ophthalmologists cannot be sure if the grafts are rich or poor in the essential stem cells.

In this study, Dr. Bruce Ksander, associate Professor of Ophthalmology at Harvard Medical School, and also of Massachusetts Eye & Ear Infirmary, and colleagues found that the gene ABCB5 acts as a marker for hard-to-find limbal stem cells, and is also essential for maintaining the stem cells and growing and repairing the cornea. They found mice lacking a functional ABCB5 gene lost their limbal stem cells, and their corneas healed poorly after injury.

Interestingly, mice deficient in limbal stem cells developed fully functioning, restored corneas, that were kept clear and normal, after receiving transplants of human ABCB5-positive limbal stem cells. In contrast, control mice that received either no limbal stem cells, or received ABCB5-negative limbal stem cells, failed to restore their corneas.

The researchers used antibodies to detect ABCB5 and confirm that tissue from deceased human donors contained limbal stem cells before transplanting them into the mice. They state ABCB5 keeps the stem cells alive, and protects them from programmed cell death or apoptosis. This study in mice is thought to be the first to show how the gene ABCB5 behaves in normal development.

References:

ABCB5 is a limbal stem cell gene required for corneal development and repair, Bruce R. Ksander, et al.,Nature, DOI: 10.1038/nature13426, published online 2 July 2014.

 

Massachusetts Eye and Ear news release accessed 30 July 2014.

 

EuroStemCell factsheet accessed 30 July 2014

 

http://www.medicalnewstoday.com/articles/279242.php accessed 30 July 2014

3. Noninvasive retinal imaging device may provide highly predictive early detection of changes associated with Alzheimer's disease

A noninvasive optical imaging device developed at Cedars-Sinai can provide early detection of changes that later occur in the brain and are a classic sign of Alzheimer's disease, according to preliminary results from investigators conducting a clinical trial in Australia.

Preliminary results showed the test could differentiate between Alzheimer's disease and non-Alzheimer's disease with 100 percent sensitivity and 80.6 percent specificity in a sample of 40 patients. The optical imaging exam appears to detect changes that occur 15-20 years before clinical diagnosis. It's a practical exam that could allow testing of new therapies at an earlier stage, increasing the possibility of altering the course of Alzheimer's disease.

The accumulation of beta-amyloid plaque in the brain is a hallmark sign of Alzheimer's, but current tests detect changes only after the disease has advanced to late stages. As treatment options improve, early detection will be critical, but existing diagnostic methods are inconvenient, costly and impractical for routine screening.

Positron emission tomography (PET) scans require the use of radioactive tracers, and cerebrospinal fluid analysis requires that patients undergo invasive and often painful lumbar punctures, but neither approach is quite feasible, especially for patients in the earlier stages of disease. PET scans are the current diagnostic standard.

The beta-amyloid plaques associated with Alzheimer's disease occur not only in the brain but also in the retina. By staining the plaques with curcumin, a component of the common spice turmeric, the researchers could detect it in the retina even before it began to accumulate in the brain. The device developed enabled them to look at the retina and see these changes.

This clinical trial was designed to enable researchers to correlate retinal plaque detected by optical imaging with brain plaque detected by PET scans. Studies involved patients diagnosed with Alzheimer's, a group with mild cognitive impairment and a group of people with no evidence of brain abnormality.

The retinal beta-amyloid plaque findings and optical imaging technology began with studies in live rodents and the post-mortem investigation of human retinas of people who had died with Alzheimer's.

This large double-blind clinical trial appears to validate this novel human retinal amyloid imaging approach using curcumin labeling. It further demonstrates significant correlation with brain amyloid burden, thereby predicting accumulation of plaques in the brain through the retina.

References:

Alzheimer's Association International Conference 2014, oral presentation: "Retinal amyloid fluorescence imaging predicts cerebral amyloid burden and Alzheimer's disease." (Copenhagen, Denmark)

http://www.medicalnewstoday.com/releases/279566.php accessed 30 July 2014

4. Spectral Edge plans enhanced video trial with Colour Blind Awareness

The technology company Spectral Edge has announced that it is working together with Colour Blind Awareness, an organisation that raises the awareness of the needs of the colour blind, to trial its new image-enhancement technology, EyeTeq.

EyeTeq uses mathematical perception models to modify image colours so that colour blind observers enjoy improved visibility, whilst at the same time minimising the strength of the effect for those who do not have colour blindness, or "colour normals".

Following a successful psychophysical study on a representative sample, EyeTeq is now being brought into living rooms and applying it to mainstream TV content. The technology company will gather direct feedback on the experience for colour blind viewers as well as colour normals. They hope the results will eventually cause consumer electronics companies delivering devices that are more colour blind friendly.

Colour blindness affects approximately 1 in 12 men (8%) and 1 in 200 women around the world. In the UK there are approximately 2.7 million colour blind people (about 4.5% of the entire population).

Applicable to both still pictures and video, Eyeteq enhances images so that colour blind observers can see details they previously could not, transforming the experience of watching TV in particular. It does this without negatively affecting the picture for colour normals, enabling both to share the same screen.

References:

http://www.realwire.com/releases/Spectral-Edge-plans-Enhanced-Video-Trial-with-Colour-Blind-Awareness accessed 28th July 2014

 

July certainly brought some exciting research. If you have any comments I would love to hear from you, my email is This email address is being protected from spambots. You need JavaScript enabled to view it.

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