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Thursday / May 23.
HomemistoryAMD: the Quest for the Holy Grail

AMD: the Quest for the Holy Grail

Scientists know that age, diet and smoking influence a person’s risk of developing macular degeneration (MD). They also know that genetics plays a strong role in determining who will get the disease – a direct family history means you have a 50 per cent risk of developing MD.Scientists know how to treat wet MD (but not dry) to slow its progression – and even how to improve visual acuity. But what they don’t know is how to cure it. In the lead up to Macular Degeneration Awareness Week (26 May–1 June), we take a look at some of the latest treatments and cures currently being explored.

Earlier this year, the Stem Cell Foundation was launched in Australia with the express aim to promote the study and use of stem cells, prevent or control diseases or illnesses and enhance public education. The Foundation’s first investment brought Dr. Kathryn Davidson, a young Australian stem cell expert who has been working in the US, back to Melbourne to work with the Centre for Eye Research Australia (CERA).

Dr. Davidson hopes to help solve the mystery of what causes age-related macular degeneration (AMD), the cause of 50 per cent of Australia’s blindness, which brings with it a cost to the country’s economy
of AUD$5.15 billion per year.1

Dr. Davidson said that rather than looking for a stem cell therapy to treat AMD, her aim is to better understand the disease, and get to a point from which treatments can be researched.

… a major advantage of gene therapy is that one dose may provide treatment for many years and possibly for life

“AMD is poorly understood, in particular what causes the death of retinal epithelium pigment (RPE) cells in the first place is not known. Therefore, our focus has been to try to come up with a better system to study AMD, where we can work to understand what happens early in the disease process. We think this knowledge will be critical in the future for developing strategies for early intervention for AMD,” said Dr. Davidson.

“Our research aims to use stem cells as tools to study disease rather than as a source of cells for transplantation. We will do this by taking skin cells from patients with known genetic risks for AMD, turn those skin cells into stem cells, then make those stem cells into retinal cells in order to study the disease in a dish.

“The diseased retinal cells we make in the lab will be compared to normal retinal cells to see how their behaviour differs; hopefully this provides insight into what is happening in an eye affected with AMD. We do not know what happens in AMD that leads to the death of retinal cell. Because AMD is a degenerative disease, cells in the eye die and we can’t study them well – we need to be able to study the disease state prior to death of the retinal cells,” she said.

“We anticipate that creating a cellular ‘model’ of the disease will allow us to better study and understand what happens during the progression of AMD, prior to when retinal cells die.”

She said a better understanding of what happens in AMD – affected cells could lead to new clinical strategies to intervene in the future. “We are in the early stages of research still. The diseased cells that we will generate in the lab for AMD could be used for drug screening in the future; but again, it is still early and we need to see where the research leads first.”

Dr. Davidson said that without basic research of this nature, there would be nothing feeding into future clinical trials, but clinical outcomes are not certain or guaranteed. “It’s important to work on many different research strategies, because we do not know which one will lead to the next clinical trial,” she said.

London Project to Cure Blindness

Stem cell research is progressing at a rapid pace in the United Kingdom where Professor Pete Coffey leads the London Project to Cure Blindness. Having satisfied major safety studies, Prof. Coffey has applied for regulatory permission to enter human clinical trials into a stem cell therapy that “would replace damaged natural cells and restore sight, prevent blindness and improve sufferers’ quality of life.” Prof Coffey’s trials will use embryonic stem cells however, like Dr. Davidson in Melbourne, his team is also looking into using adult stem cells cultivated from the patient’s own skin. “Your skin still has the blueprint of how it was developed… (so cultivating a patient’s own stem cells from their skin) will give a donor matched piece of tissue, with no risk of rejection,” said Prof. Coffey.

Unlike most research projects, which can spend 10 to 20 years in the laboratory before even moving to pre-clinical trials on animals or cell cultures, the London Project to Cure Blindness has made it to human clinical trials within just five years (subject to regulatory approval).

This was achieved by finding the funding to pull together an entire team – the clinicians, engineers, scientists and commercial organisations necessary to develop the treatment. As of February this year,
Prof. Coffey said the Project had cost well over £10million.

“That’s how complex and how expensive it is to take a therapeutic to clinic.” He said ongoing funding has “in part” been taken on by Pfizer, which has also given the assurance “that if trials go well, they will power (the project) as fast as they can into everyday clinical use.”

Professor Coffey said this is the first time a pharmaceutical company as large as Pfizer has partnered on a stem cell project.

In essence the research project aims to replace damaged RPE by a sheet of RPE cells created from stem cells. In an interview with Australian researcher Norman Swan, he said that a half hour procedure “could give you sight for the rest of your life”.

Rob Cummins, Research and Policy Manager at the Macular Disease Foundation Australia, stated that investment in research is critical to finding answers and reasons for this disease. “It is very encouraging to have large scale investment in research on macular degeneration, such as the London project. The work on stem cell research is very promising but a ‘cure’ as such is unfortunately still a long way off. Research is a journey of discovery, with the ultimate destination being a place where we can save sight. Along the way we will learn a great deal that can yield great benefit,” he said.

Mr. Cummins continued, “It is encouraging to see stem cell research across the world, but even so, it would be another five to 10 years before a treatment was potentially available to the public. Advanced Cell Technologies in the United States has initial evidence that its stem cell therapy for advanced dry AMD and Stargardt’s appears safe in humans. Very small patient trials in the UK and US have shown the treatment is stable – for instance, the implanted embryonic stem cell-derived RPE cells aren’t converting into other cells, they’re not replicating out of control and they’re remaining in place in the sub-retinal space”.

Dr. Davidson at CERA agrees that it is important for the research to proceed. “It is true that cell replacement strategies for AMD may not ultimately cure the disease; however, there are many current medical therapies that do not cure an underlying disease but rather improve quality of life and/or manage symptoms. If we set our standards for all clinical trials at the level of ‘curing’ a disease, we would end up with very few trials indeed,” she said.

“I am not a clinician, but my understanding is that there may be a window for cell therapy in AMD where doctors believe patients might benefit by replacing the RPE cells at a point in time prior to photoreceptor death. It is possible that this may only delay, but not ultimately prevent, photoreceptor degeneration later on. However, research leading up to this point suggests that the transplanted RPE cells can integrate and function, and lead to improved outcomes in rodents, which is why clinical trials for AMD are moving forward in several countries.”

Gene Therapies

Mr. Cummins said other important research is being conducted into gene therapies to manage MD that one day could see defective genes replaced or genes implanted that are encoded for the production of specific therapeutic proteins.

“There are at least 20 genes involved with macular degeneration, so the trick will be to do gene screening to identify the particular defective gene and then to do the treatment. Ultimately gene testing may help doctors to modify the treatment being offered according to the gene that is involved. But again, we’re still many years away from a product that can be made available for the public.”

He said a major advantage of gene therapy is that one dose may provide treatment for many years and possibly for life. However, there are risks attached. For example, it may not be possible to ‘turn off’ an implanted gene if its effect is no longer required or if it causes major side effects.

Laser to Stimulate RPE

More likely in the short term is a treatment being trialed by Professor Robyn Guymer from CERA. She hopes an experimental nanosecond laser-based therapy will be available to slow and even reverse MD within the next five years. The aim of the treatment is to stimulate the RPE cells that nourish the main cells in the retina.

In a pilot study, Professor Guymer delivered 12 spots of laser to one eye of each of 50 people. She found that the yellow deposits known as drusen – which are early signs of MD – that were visible at the back of each person’s eye, seemed to go away, and at the very least, did not multiply. Furthermore, after 12 months, about two thirds of patients experienced sustained improvements in visual function in the treated eye, with the majority of patients also noting an improvement in their untreated eye.

With nanosecond laser, the pulse of energy is delivered for a tiny length of time. As a result, the tissue that the laser travels through is not destroyed, so the rest of the retina is left intact.

Dr. Guymer noted that, “a patient’s visual function typically improved in the area of the eye that had the most damage. It’s this damage that typically leads to complications of AMD and subsequently, severe vision loss. In addition, the treatment appears to be safe, with research showing no evidence of laser damage to photoreceptor cells.”

In an interview on Radio National, Professor Guymer likened the function of the RPE layer to one of a cleaning agent. “Every time you turn the lights on, little membranes get shed and they’re supposed to get gobbled up by this layer of cells and then discharged into the bloodstream.”

She said this function has slowed in people in the early stages of MD and that the laser treatment she is working on appears to stimulate its activity.

“In pre-clinical studies it looks as though (the laser) causes those cells to divide. We’re not sure whether that’s the case in humans or not, yet. But by some mechanism, which we don’t understand, that layer of cells is better able to do its job, which is to get rid of the debris, which is built up in the back of the eye… it just makes that area of the retina function better, which, over time and over years, has slowed down in its ability to do its job.”1

Professor Guymer said she hopes this world first laser treatment will reverse the process of MD and stop people from experiencing vision loss before the process begins.

Reducing Risks

In 2012, Professor Paul Mitchell received a research grant from the Macular Disease Foundation to study the risk factor profile of people who are seeking treatment for late-stage age-related macular degeneration (AMD).

It is anticipated that this study will build on the invaluable data obtained from Professor Mitchell’s landmark Blue Mountains Eye Study (BMES).

Professor Mitchell will assess the impact of AMD on quality of life, identify the prevalence of AMD-specific genes and determine the primary barriers to accessing treatment. He expects it to create a greater understanding of the link between modifiable risk factors such as nutrition, body weight and smoking, and non-modifiable factors such as genetic predisposition.

As a result of this study, Professor Mitchell believes people at high risk of AMD will be more easily identified and therefore better equipped to modify their lifestyle in order to slow the progression of their disease and improve their quality of life.

Dr. Bamini Gopinath, a senior research fellow at the Centre for Vision Research, Westmead Millennium Institute is also researching dietary and lifestyle aspects of macular degeneration, under the supervision of Prof. Mitchell.

Dr. Gopinath, who was the recipient of the 2013–14 Blackmores Dr. Paul Beaumont Research Fellowship and along with further funding from the MDF, is performing a detailed analysis of the 15 year data from the BMES to improve knowledge of the nutritional and lifestyle risk and/or protective factors (particularly dietary antioxidant and supplement intake, diet quality and food groups). This is expected to help explain the causes of disease, improve early detection of people at risk of progression, and facilitate new approaches to therapy.

“There’s increasing evidence to show the importance of diet in AMD in reducing risk,” said the Macular Disease Foundation’s Mr. Cummins. For instance, he said, more than 20g of alcohol a day may increase a person’s risk of developing AMD, while eating fish and leafy greens can decrease the risk. Switching from high glycemic to low glycemic index (GI) carbs can also lower the risk. That means people at risk of MD should replace foods such as processed white bread and white potatoes with low GI foods including grains, pasta and legumes.

AREDS 1 & 2

Results from the AREDS in 2001 showed that high levels of antioxidants and zinc in people with intermediate stage AMD or late stage AMD in one eye can significantly reduce the risk of advanced age-related macular degeneration and its associated vision loss.

AREDS1 followed 3,640 patients, ages 55 to 80, in 11 medical centres across the United States. Of the patients given the high-dose supplement containing the vitamins and zinc (80mg/day), development of advanced AMD was cut by 25 per cent and the risk of vision loss was reduced by 20 per cent. These same nutrients had no significant effect on the development or progression of cataract.

Later this year, results from AREDS2 will be published. This study was commissioned in 2006, and aimed to show whether a modified combination of vitamins, minerals, and fish oil could further slow the progression of vision loss from AMD.

In the meantime, smaller studies have added further insight into the possible role of certain supplements. In February this year, for instance, a study published found that after one year of treating a patient group with lutein and docosahexaenoic acid (DHA) supplementation, the macular pigment ocular density (MPOD) in patients with early AMD had increased.2

Ginkgo biloba extract is also being carefully considered for use in slowing the progression of MD although trial results are, as yet, inconclusive. Widely used in China, Germany, and France, researchers say trials to date have been too small and short lived to provide any reliable evidence.

In response to the findings, a plethora of supplements has entered the market, which to varying degrees follow the daily intakes of vitamins and minerals recommended as a result of the AREDS. Best known are Blackmores Macu-Vision and Lutein-Vision. In 2010 Stiltec released Macutec – a supplement for AMD that was also based on the AREDS formula with the addition of omega 3, lutein and zeaxanthin. Early this year (2013), Bausch and Lomb launched Ocuvite, Ocuvite Lutein and Ocuvite Adult 50+, all of which the company claim are based on “the most current findings in eye research combined with the latest findings
in healthy nutrition”.

Existing Treatments

intravitreal anti-vascular endothelial growth factor (VEGF) injections continue to be the most effective treatment for wet AMD. These drugs work by blocking the actions of VEGF, a substance important in the development of wet AMD due to its ability to stimulate abnormal blood vessel growth underneath the retina.

Until recently, the only anti-VEGF agents available for ocular use in Australia were off label Avastin (bevacizumab) and registered and listed Lucentis (ranibizumab). Both drugs have been widely used for treating wet AMD in Australia since 2006 and 2007 respectively and have enabled a majority of patients treated for wet AMD to maintain their visual acuity.

Introduction of Eylea

On 1 December 2012 Eylea (aflibercept) was listed on the Pharmaceutical Benefits Scheme (PBS). This new anti-VEGF drug is the first major treatment for wet AMD
to be introduced into Australia in the
past five years.

According to Dr. Simon Chen from Vision Eye Institute, Eylea differs from Avastin and Lucentis in that it has a significantly higher binding affinity to VEGF and has an additional mechanism of action by blocking the effects of a substance related to VEGF called placental growth factor. Like Avastin and Lucentis, Eylea is administered via intravitreal injection.

In an article published by mivision in February 2013, Dr. Chen said Eylea has been available commercially in the US since November 2011 and early reports regarding its use have been encouraging. At the American Society of Retinal Specialists annual meeting in August 2012, 10 abstracts from different US centres were presented, all reporting favourable treatment results with Eylea for wet AMD. These included numerous reports of improved visual and anatomic results in patients who had switched treatment from Lucentis to Eylea after experiencing suboptimal results with Lucentis. Because Eylea is new to the market, we are yet to see the results of patients who are switched from Eylea to Lucentis.

For patients, the costs and injection procedure associated with an Eylea injection are identical to that with Lucentis. In the first year of treatment, the recommended treatment regimen for Eylea is by injection every eight weeks after an initial induction course of three four-weekly injections. For Lucentis, the recommended regimen is four-weekly injections, however ophthalmalogists
usually practice an ‘inject and extend’ or a ‘PRN’ (as needed) approach, based on individual response.

Recent research presented in Australia by Professor Bressler said analysis of the VIEW study, which compared ranibizumab with aflibercept, showed that at the end of two years, visual acuity results across both groups were clinically equivalent. In eyes treated with 2mg aflibercept every eight weeks, mean change in BCVA from baseline was +8.4 letters at week 52 and +7.6 letters at week 96, with a mean 11.2 injections over the two years of the study, including 4.2 injections in year two. In eyes treated with 0.5mg ranibizumab, mean change in BCVA from baseline was +8.7 letters at week 52 and +7.9 letters at week 96, with a mean 16.5 injections over the 2 years of the study, including 4.7 injections in year 2.4. For more information, see mivision’s feature The changing dynamic of MD Treatment on page 53.

In the meantime, the search continues to find a treatment to control dry MD, which is the result of complex genetic and environmental factors, and typically develops very slowly, over decades.
This makes it difficult to test the efficacy of any drugs in the test tube or in animals, let alone enter human trials.

A Genetic Disease

Macular degeneration (MD) affects the macula, a region of the retina responsible for central vision. The retina is the layer of light-sensitive tissue in the back of the eye.

MD can appear in two forms known as ‘wet’ and ‘dry’. ‘Dry macular degeneration is noted by the formation of drusen or pigment changes and over time, atrophy of the macula. Wet degeneration occurs when new blood vessels form behind the retina and subsequently rupture and leak fluid, leading to rapid vision loss.
As MD progresses, tasks such as reading, driving, and recognising faces become more difficult and eventually impossible.

An estimated one in seven Australians (that’s one million people) over the age of 50 has some evidence of MD and there is a 50 per cent risk for developing the disease for those with a direct family history of MD.
Some kinds of MD are treatable if detected early, but no cure exists – yet.


Ita Buttrose: The Face of MD

The 2013 Australian of the Year Ita Buttrose, is patron of the Macular Disease Foundation Australia and the face of this year’s Macular Degeneration Awareness campaign. For her the battle against MD is personal.

“My father was in his mid-80s when he lost his central vision to macular degeneration. It changed his life. As a journalist and author he had always started his day reading a couple of newspapers. Suddenly this was no longer possible.

“As a journalist and author myself I couldn’t imagine not being able to ever read again. I was as devastated about Dad’s fate as he was.“One of Dad’s sisters also had MD and their youngest brother was also diagnosed. Fortunately the sight of one of my uncle’s eyes has been saved with the help of a treatment for wet MD. This has been a major breakthrough in the management of the disease and my uncle’s doctor has been able to stabilise his vision. If only this treatment had been around to help Dad, how happier the last years of his life would have been.

“One thing I have noticed is how few people know that a direct family history of the disease brings with it a high risk of MD. When I tell them that I have a 50 per cent chance of getting it too, most people are usually shocked. My children are equally at risk and consequently we all do some kind of regular exercise, watch our weight and follow the eating program recommended by the Foundation.“I get my macula checked annually and when my ophthalmic surgeon tells me my ‘macula is in pristine condition’ his words are music to my ears!”


References

1. Eyes on the Future, A Clear Outlook on Age-related Macular Degeneration. Prepared for the Macular Degeneration Foundation by Deloitte Access Economics. Funded by Novartis.

2. www.radioaustralia.net.au/international/radio/program/innovations/laser-therapy-could-prevent-eyesight-loss/1046540

3. García-Layana A, Recalde S, Alamán AS, Robredo PF.
Ophthalmology Department, Clinica Universidad de Navarra, C/ Pio XII 36, 31080, Pamplona, Spain. [email protected].

4. http://bmctoday.net/retinatoday/2012/03/article.asp?f=intravitreal-aflibercept-for-amd-2-year-results

www.stemcellfoundation.net.au