Medical research takes money, and we’re grateful that BUS members continue to find imaginative ways to fundraise for research. However, research also takes time, so we thought you might like to know how some of our BUS-sponsored research projects are progressing.

Genetic control of iron levels in birdshot uveitis

What Dr Graham Wallace, University of Birmingham, wants to investigate is the association between the presence of HLA-A29 (which is carried by nearly all patients with birdshot) and an alteration in another gene which can cause iron overload in the body. Iron is essential for retinal function, and its levels are controlled by iron-regulating proteins. However, too much iron in eye tissues can cause damage. Dr Wallace intends to examine the genetic makeup of 75 birdshot uveitis patient samples from the UK Birdshot Biobank and also investigate the samples’ iron levels, looking for any connections between iron levels and birdshot. 

Doing medical research often meets obstacles. In Dr Wallace’s study, the obstacle has been a lack of birdshot patient blood samples because setting up the UK Birdshot Biobank took much longer than expected. As the number of patient blood samples increases in the biobank, the study should be able to proceed. 

We look forward to hearing more about this project.

A closer look at birdshot retinal cells

Changes in the retina occur in birdshot uveitis, particularly in the retinal pigment epithelium (RPE) cells. Until now, it has been very difficult to obtain samples of eye tissue from birdshot patients for studies. Dr Gonzales-Cordero and colleagues at University College London Institute of Ophthalmology wanted to find out if it was possible to use a technique called induced pluripotent stem-cell (iPS) modelling to generate RPE cells from birdshot patient’ blood samples. This would enable the cells to be studied in detail.

The investigators have successfully achieved this, even though the birdshot patients who donated blood samples were all receiving immunosuppressant treatment. The birdshot-derived RPE cells were found to be HLA-A29 positive, as were the birdshot blood sample donors.

These results are an exciting step forward because the iPS-derived RPE cell lines will become a continuing birdshot research resource. The researchers hope that these cell lines might eventually provide a laboratory method for testing new uveitis treatments or gene therapies. 

Are there any early signs or symptoms that predict birdshot’s course?

This is a question that, till now, has been frequently asked but for which there have been few definite answers because birdshot’s progress is very unpredictable, even when treatment is started early. Mr Mark Westcott and colleagues at Moorfields Eye Hospital, London, have studied a large number of their birdshot patients’ medical records to look for possible answers.

They found that birdshot patients who at diagnosis had either normal Humphrey visual fields, or good dark-adapted electroretinogram (ERG) test results, or the absence of retinal atrophy, were most likely to have good treatment outcomes. Reassuringly, having birdshot diagnosed at a young age, or having macular oedema and poor vision at diagnosis, did not appear to affect the chances of eventually achieving a good treatment result. 

These findings should allow ophthalmologists to be able to give newly-diagnosed patients some guidance on the possible progress of their birdshot.

Creating a Health Utility Value for birdshot

Receiving a diagnosis of birdshot, learning to live with its effects on vision and dealing with the side-effects of treatments all contribute to alterations in health-related quality of life (QoL). Professor Philip Murray and colleagues at University of Birmingham set out to identify the effects of birdshot on QoL, not only to assist doctors in understanding their patients’ problems better, but also to assist in wider official decision-making in evaluating treatments for birdshot. Creating a Health Utility Value specifically for birdshot – a patient estimate of their overall health state – would be a valuable evaluation tool.

Birdshot patients were recruited to complete a series of internationally recognised standardised QoL questionnaires. The results were combined with a set range of eye-related clinical observations made on each patient.

Preliminary results indicate that QoL is affected in birdshot patients, but not to the same extent as in patients with other types of uveitis affecting both eyes, Future studies could include asking patients to complete specific depression and anxiety questionnaires. This would add to the value of this pioneering research into QoL in birdshot.

Research Study: Genetic polymorphism and outcome in uveoretinitis syndromes (also known for short as GPOUS Study)

This is just a heads up that over the next few months, people with Birdshot Uveitis attending Moorfields and other eye clinics may be asked if they would like to take part in the above study. The aim is to get another 100 people with Birdshot from the Moorfields cohort to join in. On the particular day in June when I was asked, there was at least one other Birdshotter that I know who also took part.

The researchers are looking at a number of different eye conditions, but if they have a largish cohort of Birdshot Uveitis patients, they may well get some useful pointers as to why some cases of Birdshot are more severe than others, and why some are easier to treat. The information may well be useful in helping to determine less toxic treatment strategies.

There are a number of other participating eye hospital sites, including St Thomas’ (London), Birmingham, Bristol, Brighton and Manchester.

It is encouraging that we are managing to utilize the National Birdshot Research Network to get the various different hospitals to work together so that there are sufficient patients that can be studied in a meaningful way.

After I had donated my ’two tablespoonfuls’ of blood, I subsequently had the opportunity to quiz Professor Miles Stanford. I asked him if it would be possible for the information about Birdshotters’ DNA and blood samples to be fed into the Birdshot Database.

The answer, unfortunately, was no, but he indicated that ethical approval had been granted so that the anonymised DNA samples could be retained and used by other researchers to look at other genetic risk factors.

Here is some background information taken from the patient information sheet that the researchers gave me to read, so if a researcher approaches you when you are in the eye clinic and asks you if you are interested in participating, you have a little more information in advance.

Background and Purpose:

Uveoretinitis syndromes are a group of diseases that affect the eye and cause inflammation within it. In approximately half of the cases, the inflammation appears to be confined to the eye, and in the other half it appears in association with inflammation elsewhere in the body, commonly arthritis. It is not a very common disease and if the inflammation gets severe it may threaten vision permanently. In these cases it is necessary to treat patients with drugs which, whilst usually effective, often have unpleasant side effects or require regular hospital visits for monitoring.

We do not know why patients develop these diseases or what causes one patient to have a mild form and another to have a more severe form. Our research over the last ten years has suggested that the outlook for vision is determined in part by the genetic make up of the patient, particularly in a group of genes that control the production of molecules that either make the inflammation worse or others that make it better. It is now possible to target these molecules with specific drugs, so the ability to know whether an individual’s disease is driven by an excess of molecules that cause inflammation or by a lack of molecules that make it better is becoming very relevant for treatment.

The aim of the current research study is to relate the different genes that a patient has to the outcome of their disease at 5 and 10 years. By using various combinations of the genes we hope to produce a test that can predict the outcome of the disease in 5 and 10 years time. If we can do this then we will be able to reassure patients with a good outlook and devise more appropriate treatments for those where the outlook is less good.

 What will happen to me if I take part?

If you do decide to take part, your examination is exactly the same as would happen when you are seen in the eye clinic. After your routine eye examination, we will then ask you to sign a consent form to show you have agreed to take part and we will then take a small blood sample (2 tablespoonfuls) from you for our research study. These samples will then be available to researchers who are investigating the genes and markers that may influence the sort of eye disease that you have and its severity. We will also require your medical history from your GP or hospital records and we will continue to monitor your disease’s progress over 10 years. We will let your GP know that you have agreed to take part in the study

What are the side-effects and possible disadvantages of taking part?

If you take part in the study you will spend longer in the clinic than if you do not, as the doctors will be spending time explaining the study to you and taking the blood sample. There are no other disadvantages to taking part in the study.

What will happen to the blood sample?

The blood sample will be processed in the laboratory to extract the genetic material (DNA) from the cells. This DNA can then by analysed to look for genes that we think may have an effect on the risk of developing uveoretinitis. Your sample will then be frozen in a locked freezer in a secure laboratory.

What will happen to the results of the study?

Any results that emerge from the study will be published in scientific and medical journals. The results from the study will be anonymous and the identity of individuals taking part will not be declared. It will not be possible for you to learn of the results of tests on your blood sample in this study.

 Who is funding the research?

The research is being funded by a grant from the Guide Dogs for the Blind Association and the research will be carried out jointly between St Thomas’ Hospital and the University of Birmingham. Future studies on the blood samples from this collection will be undertaken by various other groups and funded separately. The future use of your sample in other studies will only be allowed if ethical approval for individual projects had been obtained first.

How long will the research last?

The aim is to record how your eye disease progresses over a 5 year period to determine the eventual outcome. We already know from previous studies that the vision at this time predicts the outcome at 10 and, in some cases, 15 years. It is intended that the large number of blood samples generated from this collection will be available for many years afterwards to doctors and scientists as more genes that might cause or influence the severity of uveoretinitis are discovered. However, the identity of the people providing the blood samples would remain unknown to them.

Gill said: “They were very interested when I said that there may be other birdshot patients here in Victoria and beyond. If you are in Australia and  interested in taking part (a simple blood test so far) could you let me know via Annie at Birdshot Uveitis Society info@birdshot.org.uk.”

BUS has subsequently been in touch with the researchers involved in the study and heard back from Alex Hewitt who said:-

(Note: the whole paper can be downloaded as a pdf by following the link above and scrolling to the bottom of the abstract.)

This paper provides a comprehensive summary of current  tests and treatments available for Birdshot Uveitis.  It clearly makes the important point that, although central visual acuity can be preserved until late in the disease, it is not uncommon for patients to receive inadequate immunosuppressive treatment, leading to a poor long-term outcome in which peripheral retinal damage eventually leads to visual deterioration.

It also states that  although “laboratory research continues to investigate the underlying mechanisms of disease, and clinical research is now being driven to improve the phenotyping and monitoring of this condition, it is becoming increasingly important to identify patients at risk of visual loss early so that they can be treated more aggressively with targeted therapies such as the newer biological agents.”

It states that “this approach requires the formation of collaborative groups, as the relative rarity of the condition makes it difficult for one center to accumulate enough patients for worthwhile studies. Nevertheless, results obtained with newer therapies, such as biological agents directed against particular cytokines or cell-surface receptors, demonstrate ever improving control of the inflammation in refractory cases, providing hope that the outlook for visual function in this condition can only improve.”

This paper certainly gives BUS hope.  It is gratifying that it clearly endorses our belief about the best way forward, just at the point when we are getting collaborative work off the ground with the National Birdshot Research Network; and the development of the Birdshot bio-resource centre and Birdshot database.

 1)    the development of a National Birdshot Bio-Resource Centre and;

 2)    the development of a National Birdshot Uveitis Registry.

These two projects are coming to fruition thanks to the hard work of Birdshot Uveitis Society supporters who have helped raise the money and also thanks to the imagination, ingenuity and resourcefulness of clinicians and research scientists who are involved in the National Birdshot Research Network.

The Bio-resource Centre project is being jointly funded by BUS and Fight for Sight, the main UK charity dedicated to funding eye research to prevent sight loss and treat eye disease, via a jointly funded Small Grant Award of £15,000.  50% of the costs has been raised by Birdshotters who took part in the 2012 Carrots Nightwalk, a six and 15 mile charity walk, with matched funding from Fight for Sight.

 The development costs of the National Birdshot Uveitis registry is being funded by BUS with money our supporters have donated over the last year and donations from the BUS 2013 Shoot which is our major fundraiser.  This award will be administered by Fight for Sight.

Thank you so much to everyone for your time and generous support. We wouldn’t have got this far without it!

World’s first birdshot uveitis biobank project

This research proposal is one you may have previously seen mentioned here: establishing in the UK the world’s first birdshot uveitis biobank. Biobanks collect and store donations of anonymised patient samples of blood, urine and other tissues. Approved researchers can then use these materials, feeding back their research data to the biobank. This adds to the original information held about the samples, which increases their usefulness to future researchers.

Rather than set up an independent birdshot biobank, it makes economic sense to use an existing biobank. The established Infectious Diseases Biobank at King’s College Hospital, London, has expanded to include collections of samples from patients with inflammatory conditions. This means that the Birmingham-based researchers’ proposal to set up the birdshot biobank within the biobank at King’s College Hospital fits in well with King’s existing work.

The project will start by recruiting a small number of birdshot patients from St Thomas’ Hospital, London, Moorfields Eye Hospital, London, and the Birmingham and Midlands Eye Centre, to donate samples to the biobank.

Clinical data from the National Birdshot Uveitis Registry (see below) would accompany the biobank samples. The combined resources of the National Birdshot Uveitis Registry and the National Birdshot Biobank would enable a great variety of statistically-valid and useful studies to be performed on large numbers of birdshot patient samples.

It is hoped that the birdshot biobank will eventually provide the opportunity for all UK birdshotters to contribute to research by donating their samples. Our involvement will provide the keys to help researchers start to unlock some of the mysteries of birdshot and to improve its treatment.

Developing a UK-wide National Birdshot Uveitis Registry

To be statistically significant, medical studies need to be done on large numbers of patients. Because birdshot is a rare disease, it has been difficult up to now to recruit enough patients to do useful research. Although large studies of up to 80 birdshot patients have been carried out in several European centres, similar scale studies have not been conducted in the UK, principally because birdshot patient information is not held in one place. Creating a national registry database of UK birdshot patients would provide a resource of information on birdshot which would have many potential uses.  

The proposed National Birdshot Uveitis Registry (NBUR) will collect and hold clinical data on birdshot patients centrally, including test results such as angiograms and OCT scan images. From the initial pilot study involving data from a few patients at University Hospitals Birmingham and the Birmingham and Midland Eye Centre, the eventual aim is for all UK birdshot patients to be invited to register with the NBUR.

The first step in the proposed study will be to develop a patient details database at University Hospitals Birmingham, test it and perform some data analysis. The database will then be tried out with data from a small number of Birmingham birdshot patients, then modified as necessary, and then piloted at National Birdshot Research Network partner sites in the UK.

One use of the registry data will be to accompany the samples sent to the UK birdshot research biobank (see above). Other proposed uses for the data include identifying patients suitable for clinical trials, collecting drug safety data, especially for newer treatments, and eventually being able to identify ‘best practice’ and promote better care by enabling treatment centres to compare the progress of their patients within the context of a national picture.

University Hospitals Birmingham already develops and operates national databases through their established Rare Disease Service, so this experience will be invaluable in setting up the National Birdshot Uveitis Registry.