Focus Newsletter - Summer 2016

focus

Epilepsy Research UK Newsletter

A shared commitment It is my great pleasure to introduce this latest edition of Focus, which features the six new projects we have been able to add to our research portfolio this year.

As always, the projects selected for funding cover a wide range of topics, from the role of the immune system in the generation of seizures to the link between sleep problems in infants with epilepsy and their social and cognitive development. Full details of all the grant awards are given later. We are confident that these studies will make a significant contribution to our understanding of epilepsy.

The funding of our research is only made possible by the extraordinary dedication of our supporters. We were honoured to have over 700 people representing us in the recent British 10K London Run; to see so many runners in Epilepsy Research UK vests was an uplifting and wonderful sight. Many of you have taken on organising a fundraising event or participating in a sporting challenge during the year, others have contributed through donations or gifts of your time. However you are able to support our work, your generosity is always most gratefully received.

At our recent reception at No 11 Downing Street, kindly hosted by George Freeman MP, there was a tangible sense of shared commitment between our researchers and supporters to make a real difference to the lives of people with epilepsy through research.

The Epilepsy Research UK team looks forward to joining together with supporters again at our 25th Anniversary Gala Ball on 12 November 2016 at the Grange St Paul’s Hotel in London.

This is the last newsletter I will introduce, as I am leaving Epilepsy Research UK at the end of July to pursue new challenges in my career. It has been a privilege to work with you all in taking Epilepsy Research UK forward over the last 15 years. Together, we have shaped the charity into the leading independent funder of epilepsy research in the UK today. In doing so, we have made many important advances that bring new hope and that improve the lives of people with epilepsy. I wish you well and every success for the future.

Leigh Slocombe, Chief Executive

Summer 2016

RESEARCH GRANTS AWARDED IN 2016 The immune system and epilepsy Dr Sukhvir Wright Aston University and Birmingham Children’s Hospital Fellowship award of £211,011 “This research will increase our understanding and knowledge of how the immune system may be implicated in the production of seizures.”

Dr Sukhvir Wright Background The immune system protects the body from harmful agents, but occasionally it mistakenly produces antibodies that destroy normal, healthy cells/tissues. This is called ‘autoimmunity’, and the antibodies are known as ‘autoantibodies’.

Autoimmune diseases are often treated with drugs that dampen the body’s immune response (immunotherapy), such as steroids. Some people with epilepsy respond well to steroids, and this has led scientists to believe that some forms of epilepsy might be autoimmune.

To date, a number of epilepsy ‘autoantibodies’ have been identified, but how they cause epilepsy is not known. The ways in which immunotherapy works to control seizures is also not clear. Steroids have a lot of unwanted side effects that limit their use, particularly in young children, and more targeted treatments are needed. These can only be developed once a better understanding of autoimmune epilepsy has been gained.

The study Dr Sukhvir Wright’s fellowship will focus mainly on an epilepsy-linked antibody known as ‘NMDAR-Ab’, which targets protein structures called NMDARs that are crucial to making neurons ‘fire’. Current thinking is that NMDAR-Abs particularly target NMDARs on inhibitory neurons in the brain, blocking their function. The effect is too much excitation of neurons and a risk of seizures.

Dr Wright and her team will use a range of methods, in both epilepsy models and human brain tissue, to examine how NMDAR-Abs affect NMDARs and cause epileptic activity. They will then take a number of steroid compounds and examine how these ‘rescue’ NMDARs and control seizures.

Significance The findings from this fellowship will hopefully lead to the refinement of immune-targeting drugs, so that they are effective but with minimal side effects. This could happen in as little as 3-5 years, and it will greatly improve quality of life.

Dr Wright’s fellowship has been supported by our memorial funds. We would like to thank all our memorial fund supporters for their tremendous commitment and generosity over the past year.

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Investigating a new model of genetic epilepsy Professor David Wyllie University of Edinburgh Project grant of £137,230 “Individuals who carry mutations in genes that encode receptors activated by glutamate can suffer from a variety of disorders, many of which are associated with epilepsy. This project funded by ERUK allows us to extend our (previous) work to a pre-clinical model that is a direct correlate of epileptic encephalopathy.”

Professor David Wyllie Background Neurons communicate with each other using special chemicals known as neurotransmitters, which are classified as being either excitatory (meaning that they cause neurons to ‘fire’), or inhibitory (meaning that they cause neurons to stay ‘silent’). The main excitatory and inhibitory neurotransmitters in the brain are called glutamate and GABA respectively, and they act via protein structures called receptors (which they ‘activate’). A fine balance between excitation and inhibition is needed for the brain to function

A new approach to treating temporal lobe epilepsy Dr Alfredo Gonzalez-Sulser University of Edinburgh Fellowship award of £250,000 “Forward-thinking strategies for the most difficult-to-treat types of epilepsy are desperately needed.

I will test whether controlling the activity of entire seizure-generating networks, as opposed to just the seizure foci, can be a more effective treatment to block seizures.”

Dr Alfredo Gonzalez-Sulser Background Temporal lobe epilepsy (TLE) is the most common form of epilepsy seen in adults, and it is characterised by seizures that originate within a unit of structures (including the hippocampus) known as the hippocampal formation. This network plays a crucial role in memory, spatial awareness and the control of attention.

TLE is difficult to treat with existing antiepileptic drugs, and surgical methods are too often neither appropriate nor effective.

Current therapies also carry a significant risk of adverse side effects, which can impact greatly upon a person’s quality of life. There is an urgent need for better,

properly. If, for some reason, there is too much excitation, signalling becomes uncontrolled and there is a risk of seizures.

The study Mutations in a gene called GRIN2A, which encodes a protein called GluN2A, can lead to a reduction in a type of receptor that is activated by glutamate. This can make people more susceptible to epileptic seizures, but the mechanisms of this are not clear.

Professor Wyllie and his colleagues have managed to genetically engineer a rodent model that mimics the effects that a loss of GluN2A has. They now plan to use this model to record the small electrical signals generated when glutamate acts at its receptors, in order to: • investigate how signalling is altered when GluN2A expression is reduced • determine what interventions can be used to correct this altered signalling and potentially reduce the incidence of seizures Significance This research will give detailed insights into how neurons communicate in the hippocampus (an important memory structure in which seizures frequently originate), at both single cell and circuit levels. It is a knowledge-gaining project, but the findings could pave the way for the development of new epilepsy treatments in the next 10-15 years.

more targeted treatments for TLE that are more widely effective and have fewer unwanted effects.

Cell transplantation to treat epilepsy

Optogenetics is a cutting-edge technique that allows researchers to control the activity of specific sets of neurons using light. It is a highly skilled method that is being used around the world to increase our knowledge of epilepsy. Clinical trials using optogenetics to treat other conditions, such as blindness, are also underway.

Professor Liam Gray Cardiff University Pilot grant of £30,000

The study During this fellowship, Dr Gonzalez-Sulser will focus on an area of the brain called the medial septum, which has a powerful influence over the activity of the hippocampal formation. He will use optogenetics to control select populations of medial septal neurons, to try and block seizures in the hippocampus of animals with TLE. One of the advantages of targeting the medial septum is that it could be used to modulate the entire network of neurons that generate seizures in TLE, not just the seizure focus (where seizures originate). This will potentially yield a more effective treatment with fewer adverse effects.

Significance If successful, the findings from this fellowship could potentially lead to a new treatment for TLE in the next 15-20 years.

The study will also increase our knowledge of brain circuits in epilepsy, which could improve existing treatments such as gene therapy and deep brain stimulation.

transforming lives through research

“This is an exciting project that will give significant insights into the feasibility of cell transplantation for treating seizures and cognitive problems in patients with temporal lobe epilepsy.”

Professor Liam Gray Background The loss/dysfunction of inhibitory neurons called interneurons in the hippocampus of the brain is one of the earliest changes in temporal lobe epilepsy (TLE). In theory, it should be possible to replace lost/damaged interneurons with new ones, and experimental attempts to do this have been promising. Researchers have successfully transplanted human stem cells that generate interneurons into the brains of epileptic mice, and they have seen a 90% reduction in seizures.

However, the animals used in these studies did not have functioning immune systems, which was necessary to ensure they did not reject the transplanted cells. In human TLE the hippocampus is very inflamed, and long-term suppression of the immune system is not feasible. If this is to become

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a realistic treatment for TLE, researchers must understand what signals are exchanged between the inflamed hippocampus and transplanted cells in humans, and how this affects the survival, development and integration of the new interneurons.

The study A 3D cell culture is an artificially-created environment, in which cells are permitted to grow or interact with their surroundings in three dimensions. It is a very useful tool for studying the functions and interactions of different cells/tissues in health and disease. Professor Gray and colleagues have recently developed 3D cultures of human epileptic brain tissue.

These survive healthily for 6-8 weeks and show all of the hallmarks of inflammation seen in TLE. The team has added human stem cells to these cultures, and has found that, although many die, some survive and show signs of early maturation.

During this grant the group will try and identify the optimum conditions for survival and development of the transplanted cells.

Significance This study will be vital to the progress of this treatment to human clinical trials in TLE, which Professor Gray believes could potentially be in the next 3-5 years.

Is inflammation in tuberous sclerosis a sign of epileptic activity?

Professor Alexander Hammers King’s College London Pilot grant of £30,000 “If the new PET-MRI scanner methods help us find where these patients’ seizures come from, many more will be able to undergo surgery in the future.” Professor Alexander Hammers Background Tuberous sclerosis is a rare genetic condition that causes growths called tubers to form in different parts of the body. Due to the frequent involvement of the brain, most people with tuberous sclerosis also develop epilepsy, and this is often resistant to anti-epileptic drugs.

If a seizure-causing tuber is identified, it can potentially be removed surgically; however the process of identification is complex and invasive. This limits the number of people who are referred for surgery.

The link between sleep problems in epilepsy and socio-cognitive development Dr Manuela Pisch University College London Pilot grant awarded of £29,938 “Our data will indicate whether offering a standard sleep assessment for newly diagnosed infants would be a low-cost and effective way to avoid cascading consequences of early sleep problems on subsequent socio-cognitive development.”

Dr Manuela Pisch Background Sleep problems early in life are linked to poorer cognitive and social development (socio-cognitive development). Infants with epilepsy often experience sleep problems, but so far the association between epilepsy-related sleep problems and socio-cognitive development has not been investigated in this age group.

The study Dr Pisch, with colleagues at Great Ormond Street Hospital, aim to explore 1) whether epilepsy type influences the nature of the sleep changes seen in infants, and 2) whether different types of sleep change have different effects on socio-cognitive development.

The study Studies have revealed that tubers removed during surgery show signs of long-standing inflammation. Here, Professor Hammers and his colleagues want to find out if inflammation in tubers is in fact a marker that can be used to pinpoint those that are capable of inducing seizure activity. This would be a lot easier and less arduous for the patient than looking for signs of epileptic activity in tubers directly.

The team will use a combination of imaging techniques called PET and MRI to look for inflammation in brain tubers, in 12 people with tuberous sclerosis and drugresistant epilepsy, aged between 10 and 45 years. For each subject, tubers that show evidence of inflammation will be carefully mapped, and information from detailed EEG scans (which record electrical activity in the brain) will be used to find out if the locations of the inflamed tubers correspond with the areas in which seizures are occurring.

Significance If the results of this pilot grant suggest that inflammation in tubers is a reliable marker of epileptic activity, and these findings are confirmed in further studies, PET-MRI imaging could potentially give many more people with tuberous sclerosis the chance to benefit from surgical treatment. The impact of this funding could be seen in the next 3-5 years.

The researchers will recruit the families of infants with newly-diagnosed epilepsy, and will visit them twice during the project: once within two weeks of diagnosis and again when the child is 12 months old.

At both visits the infant’s cognitive, language, movement, memory and information processing abilities will be assessed.

Details about the child’s epilepsy, including their seizure frequency and treatment regimen, and information about the parents’ well-being, will also be obtained. At visit one, parents will be asked to complete a questionnaire asking about their social and economic circumstances. This will be used to help ensure that any associations made during the project are due to sleep variation and not other factors.

At the first visit parents will be trained to use an actigraph (a wrist-watch/ankle device that monitors the nature and quality of sleep), and they will be asked to record their child’s sleep over one week. They will also be shown how to complete a sleep diary for their baby. All sleep information will be sent to the investigating team.

The researchers will examine the data for patterns of abnormal sleep in different forms of epilepsy, and links between any sleep variations found and socio-cognitive development scores. They will use existing ‘normal’ sleep data from infants without epilepsy for comparison.

Significance The findings of this pilot grant could ultimately lead to the development of sleep interventions that significantly improve outcomes for infants with epilepsy.

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Reception at No 11 Downing Street

Fundraisers in action

The Rt Hon David Cameron MP was a very welcome guest at Epilepsy Research UK’s annual supporter reception, where he spoke movingly of his own experience as a parent of a child with epilepsy. The event, held at No 11 Downing Street during National Epilepsy Week, was kindly hosted

by Under Secretary of State for Life Sciences, George Freeman MP. The evening was a welcome opportunity for Epilepsy Research UK (ERUK) to thank supporters for their commitment to the charity, and to hear first-hand from this year’s six new grant recipients.

The charity was also delighted to introduce its new Ambassador, Jonathan Thomas, former Welsh international rugby union player, who has generously offered his support.

Dr Graeme Sills, Chair of ERUK, expressed warm thanks to the guests for their generous contributions to ERUK’s vital work saying, “Everything that we do - and all of the research that we fund - is the result of donations, legacies, and fundraising by you and people like you. We simply wouldn’t exist without your dedication and support.” Dr Sills spoke also of how the researchers’ energy, ideas and determination to better understand epilepsy gave hope for the future.

Thank you to everyone who fundraises for us with such incredible drive and ingenuity. Your efforts are vital to our research funding and we thank you along with all those who support your activities so generously. Here are some of our recent fundraisers in action.

National Epilepsy Week This year we continued our theme of ‘Transforming Lives Through Research’ for National Epilepsy Week (15 - 21 May), and were delighted to announce the recipients of our 2016 research grants during the week. The research grants awarded are featured in detail in this newsletter.

Supporters around the country organised and took part in various events to mark the occasion. These included coffee mornings, afternoon teas, collections, evening fundraisers and awareness-raising displays. Local to our office, groups in Chiswick Town Hall also raised awareness for us throughout the week, and our local Waitrose featured us in their Community Matters scheme throughout the month. Thank you all for your fantastic support and engaging with the week’s activities with such energy and enthusiasm!

The new grant recipients gave the guests a brief outline of their research projects, and greatly appreciated the opportunity afterwards to talk to supporters about their research, and to hear about the strong motivations behind their support of the charity.

We would like to thank our host George Freeman MP, and everyone who came to the reception for their contribution to such an inspirational evening.

25th Anniversary Gala Ball

A raffle and auction will be running We really hope that you will be throughout the evening, giving you the able to join us for an evening chance to win some fantastic prizes. of fine dining, fun and It is shaping up to be a wonderful fundraising, and help us event and we would love you to celebrate our join us!

WE’RE LOOKING 25th anniversary.

FORWARD TO Tickets for the Gala Ball

CELEBRATING

There’s still time to reserve tickets for our spectacular Gala Ball, on Saturday 12 November 2016 at the 5* Grange St Paul’s Hotel, London.

are £100 each and can be The evening will begin with a OUR 25TH booked individually or in drinks reception followed by a ANNIVERSARY tables of 10. To make your sumptuous three-course meal with IN STYLE! booking contact jo@eruk.org.uk wine. We will end with a fabulous live or phone 020 8747 5024. You can band, Down for the Count Swing also download the booking form Orchestra, who will be bringing the great from our website. sounds of the Swing Era back to life!

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BRITISH 10K LONDON RUN What an absolutely amazing day we had as the official charity at the British 10K London Run on 10 July! We were so proud of all our runners and cheering team – you could not have done more for us. Thank you Team ERUK !

“This was my first ever 10km and it was a privilege to run as part of Team ERUK, fundraising for such a fantastic cause! I was so proud to wear my green vest and to be cheered on by all of the amazing supporters - the atmosphere was incredible and I can’ t wait to sign up for my next race...”

“London 10k is the best one I’ve done by far!

Iconic route through the heart of our capital with an atmosphere that literally carries you round!”

“It was a great event, well organised and excellent for both experienced and new runners.”

“Fantastic venue with the best sights and such amazing enthusiastic support throughout. Loved it.”

“Wh at a lovely race! “

“We had a great day on Sunday - it was wonderful to spot the other Epilepsy Research UK runners and give each other a thumbs up. It was also great that the ERUK supporters were at a place where we went past them twice so we got twice the love.“

“My brother has epilepsy, he called me to say how proud and pleased I made him by running the British 10K: “It means a million to me”. Well that sums up how I feel running and raising money for an amazing charity.”

“Awesome day and the best decision I could do is to run for Epilepsy Research UK.”

sure that was “I beat my Personal Best and I am the Epilepsy ng seei as a result of the extra boost

Researc h UK team cheering me on.”

“This race made me finally believe in me and my ability to overcome...incredible day.”

“Running the British 10k for Epilepsy Research was a privilege.

The team at the charity provided lots of motivation in the run up which helped me to focus on training and raising sponsorship.”

Pre-registration is already open for next year’s race, so whether you want to run again or join us for the first time, contact jo@eruk.org.uk for details.

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SPORTING EVENTS Thank you to all our fantastic sporting fundraisers! We’re so grateful to you, and to all your many generous sponsors, for everything that you do to support our research. Here are some of Team ERUK in action recently.

SPORTING & CHALLENGE EVENTS 2016 - 2017 We would love you to be involved and join Team ERUK! Guaranteed entry is still available in the events below: • Big Fun Run – various dates July – October • Bournemouth Marathon Festival - 1 & 2 October • Great Birmingham Run – 16 October • Spartan Race – various dates You can also join our UK challenge teams!

• Thames Bridge Trek – 10 September • Thames Path Challenge – 10 & 11 September See our website for Overseas Challenges.

Registrations and enquiries are now open for events and challenges throughout 2017.

If you have your own place in any event you can still fundraise for us! Just contact us with your details to request your fundraising pack and running vest.

To sign up or register your interest, see our website or email jo@eruk.org.uk.

Christmas card shop volunteers needed We’re looking for volunteers to help in charity Christmas card shops later in the year in locations such as Bath, Durham, Honiton, London, Stamford and York. If you would like to join our team of volunteers and could spare a regular morning or afternoon each week from mid-October to mid- December to help, please contact Shona for more information, tel 020 8747 5024, email shona@eruk.org.uk.

Thank you to all our supporters for your generous donations in recent months.

Our particular thanks go to all who have chosen to remember their loved ones by supporting our research. Names of those in whose memory we have recently received donations are given on our website: www.epilepsyresearch org.uk/ support-us/given-in-memory

“Research into epilepsy is the only way that things will get better for those who live with it.”

Mark Blackshaw

If you would like to help us fund more research in the future by making a regular or single - gift, please complete and return the donation form enclosed or donate online at www.epilepsyresearch.org.uk. Thank you.

PO Box 3004, London W4 4XT T: 020 8747 5024 E: info@eruk.org.uk W: www.epilepsyresearch.org.uk • Registered charity number: 1100394 Designed and printed by Eclipse Creative Ltd: 01252 517341 www.eclipse-creative.co.uk