Euro-ataxia Annual Conference 2019 The Annual Euro-ataxia research conference took place on 15 May 2019 in Sheffield, UK. Representatives from 10 European patient organisations attended, as well as speakers from academia and industry. Professor Marios Hadjivassiliou - ‘Overview of non-inherited ataxias, including gluten ataxia’ Professor Marios Hadjivassiliou is a Consultant Neurologist at the Sheffield Ataxia Centre, with a particular interest in the neurological manifestations of gluten-related diseases. Marios presented his work in the field of non-inherited ataxias, including gluten ataxia and primary autoimmune cerebellar ataxia (PACA). The majority of ataxias (80%) are sporadic (no family history). Whilst some (about 14%) will still have a genetic cause, the majority do not. Some of these ataxias are degenerative (eg cerebellar variant of multiple system atrophy) but thanks to extensive research, we are beginning to understand what causes some sporadic ataxias, and it seems that a number of these causes are potentially treatable. The cerebellum – the region of the brain that degenerates in ataxia – can be the target of immune-mediated conditions. This occurs when a person’s immune system attacks an area of the body, after wrongly identifying it as a threat. If the immune system wrongly identifies the cells in the cerebellum as a threat, these cells will be destroyed. Primary Autoimmune Cerebellar Ataxia (PACA) occurs when the immune system attacks the cerebellum, with no known trigger. It is possible that this form of ataxia could be treated with immunosuppressant drugs, which dampen down the immune response, reducing the attack on the cerebellum. In some people who have gluten sensitivity, eating gluten can also start an immune-mediated reaction that primarily targets the cerebellum. Whilst the digestive symptoms of gluten sensitivity are more well-known (as in coeliac disease), ataxia is also a common manifestation of gluten sensitivity. Professor Hadjivassiliou estimated that 20% of all progressive ataxias could be caused by gluten sensitivity. Blood tests measuring the antibodies involved in the immune response against gluten can aid diagnosis. However, the test routinely carried out at most centres in the UK is specific to Coeliac Disease (those patients who have bowel inflammation) and will miss the diagnosis of gluten ataxia in up to 60% of patients who potentially have a treatable ataxia. Another test, which measures anti-gliadin antibodies, is currently the most sensitive test to diagnose gluten ataxia but is only available at the Sheffield Ataxia Centre. Professor Hadjivassiliou argues that if the anti-gliadin antibody test was routinely available, more people would be diagnosed with gluten ataxia, and could be treated by starting a strict gluten-free diet. Finally, a new antibody test that may be specific to gluten ataxia (antibody to TG6) has recently become available at the immunology lab, Sheffield Teaching Hospitals NHS Trust. Dr Julie Greenfield – ‘Overview of SCA Global and ARCA Global initiatives’ Dr Julie Greenfield, Ataxia UK’s Head of Research, spoke about the launch of global initiatives SCA Global and ARCA Global. SCA Global is a worldwide collaboration focusing all ataxias that are inherited in a dominant way: not just the common SCAs (eg SCA1, 2, 3, 6 and 7), but also the rarer SCAs and conditions such as DRPLA. ARCA Global is a similar initiative but for the recessively inherited ataxias (not including FA or AT). These initiatives are necessary in order to better understand the manifestation and progression of ataxia, and to facilitate clinical trials and research. This is particularly important for the rare forms of ataxia as there are so few people in each country who are eligible to participate in clinical trials. Ataxia clinical specialists and patient groups will participate in order to build the database, and standardise the ways in which clinical data is collected. Working Groups will look at topics such as clinical outcomes, biomarkers, biosampling, and global policies. Steering Committees for both initiatives have been set up, with Julie representing Euro-ataxia on both. The first SCA Global conference took place in Las Vegas in March 2019, and was attended by 120 researchers from 18 different countries. The conference consisted of research talks, poster presentations and Working Group discussions to plan how SCA Global will operate. Ataxia researchers from universities worldwide contributed, and there was significant interest from biotech and pharmaceutical companies who both sponsored the event and actively participated in the conference. The first ARCA Global conference is planned for 2020. Cathalijne van Doorne - ‘Representing Euro-ataxia in European Committees’ Cathalijne van Doorne is the President of Euro-ataxia, as well as a representative of ADCA Vereniging Nederland. She gave an overview of the various committees to which she belongs, and how she works hard to represent the ataxia community in Europe. The European Medicines Agency (EMA) regulates and approves medicines for use across Europe. Within the EMA, Cathalijne belongs to the Pharmacovigilance Risk Assessment Committee (PRAC). This Committee is responsible for assessing and monitoring the safety of human medicines, and Cathalijne represents patients’ organisations on the Committee. As Vice-President of the European Federation of Neurological Associations (EFNA), Cathalijne described their focus for this year, which will be younger people affected by neurological disorders. They are working towards reducing the stigma associated with neurological conditions, and focussing on how young people affected by brain, mind and pain conditions can get into work. They recently released their updated Book of Evidence, which is a strategic plan for how to deliver better care for people with neurological conditions in the EU. Cathalijne talked about some twitter campaigns she is currently involved in, including #BrainLifeGoals. The #BrainLifeGoals campaign will raise awareness of the impact of neurological diseases by exploring the dreams and aspirations of those living with a brain disorder. Sharing #LifeGoals has become a popular trend in social media. #LifeGoals are the often frivolous wishes people have – for example to own a designer handbag, meet a particular pop star or drive a Maserati. In this campaign they will put a new spin on the #LifeGoals trend by instead sharing #BrainLifeGoals. Those living with brain conditions do not necessarily have the luxury of frivolous dreams. Theirs are more fundamentally important things – perhaps to walk without pain, to have access to employment, or to live a life free of stigma. Cathalijne spoke about the importance of involving patients in research. She has spoken about this previously at the European Parliament, where she used the example of ataxia to demonstrate that patients and researchers don’t always agree on the most important outcome for research. Many people with ataxia say the thing they fear the most is losing the ability to speak or see. Researchers, however, often focus on the distance patients can walk. Since giving this talk at the European Parliament, Cathalijne has learnt that some pharmaceutical companies have started using the example of ataxia to demonstrate the importance of patient involvement. Professor Subramony - ‘Advances in treatment of the ataxias’ Professor Subramony is a neurologist in Florida, with a special interest in neuromuscular diseases and neurogenetics. He spoke about exciting developments in the field of gene therapy in the treatment of the ataxias. Friedreich’s ataxia (FA) is caused by a mistake (or mutation) in the frataxin gene. Gene therapy, a possible treatment option, involves replacing this mutated gene with a non-mutated version. A significant hurdle to overcome in the field of gene therapy is how to transport the non-mutated gene to the correct region in the body, and how to avoid it being destroyed on the way. Professor Subramony discussed a virus, known as AAV, that is currently the best known vector. AAV is not toxic to humans, cannot replicate, and doesn’t insert the new DNA into the genome of the host; which are all useful properties when planning gene therapy studies. He showed evidence that the AAV vehicle can be used to deliver the frataxin gene to mice with FA, and that this improved their movement. Some of the spinocerebellar ataxias (SCAs) are caused by mutations in genes, which result in the production of harmful proteins. Professor Subramony talked about the ways in which such genes could be “knocked down”, to prevent production of the protein. There are still problems to be overcome when planning to test these treatments in the clinic. For example, the virus vehicles are difficult to manufacture in large quantities, and there is the possibility that people react to these vehicles as they would to a harmful virus. However, there are a number of pre-clinical studies ongoing in gene therapy, and this is a promising area of research. Professor Chris Miall - ‘Shocking and shaking the cerebellum’ Professor Chris Miall is a Professor of Motor Neuroscience at the University of Birmingham. He studies the role of the cerebellum in motor learning, and spoke about stimulating the cerebellum as both an experimental manipulation and a potential treatment for motor conditions. Transcranial electrical stimulation (TES) is a method by which a very low intensity current is passed through the brain, simply by placing electrodes on the scalp. This current does not directly activate or damage neurons, but rather increases or decreases the chance that they will activate. This current can be targeted specifically to the cerebellum (i.e. ‘Shocking and shaking the cerebellum’). Professor Miall showed evidence that people who receive this stimulation to the cerebellum are capable of learning simple motor tasks more easily. This suggests that motor function can be improved using this technique, and indeed it has shown success in improving motor function in a number of conditions, including Parkinson’s Disease, Cerebral Palsy and spinal cord injury. A small clinical trial of 19 patients with ataxia also demonstrated that symptoms could be improved by TES. Improvements could be seen for up to three months. Ataxia UK is currently funding a further study, to determine whether repeating the treatment could extend the effects for longer than three months. As an example of another experimental brain stimulation technique, Professor Miall also showed evidence that the cerebellum is involved in cognition. Although impairments in cognition are not always associated with ataxia, there is some evidence to suggest that it does sometimes occur. He described how one can measure how fast a person is able to process spoken language by measuring their eye movements. If someone looks at the image (below), and hears the phrase ‘The man will watch the boat’, their eyes will move to the picture of the boat as the word boat is spoken. However, if the same person hears the phrase ‘The man will sail the boat’, their eyes will move to the picture of the boat upon hearing the word ‘sail’. This shows a level of cognitive processing, because the person is able to rapidly predict what the sentence will be about, before even hearing the word boat. If the person taking the test has problems with cognitive processing, the time it takes for them to look at the image of the boat will be longer. Professor Miall showed that following transcranial magnetic stimulation (TMS), the response times did get longer, implicating the normal cerebellum in language processing. At the moment, however, there is no strong evidence that TMS can alleviate clinical symptoms. Professor Dagmar Timmann - ‘Management of the ataxias’ Professor Timmann is a neurologist based in Essen in Germany, and she runs a very active research laboratory. Professor Timmann spoke about how the diagnosis and management of the ataxias has changed over the years, and the current best practice for treating the ataxias. Professor Timmann started with an interesting overview of how the diagnosis of ataxia has changed over the last 30 years. Today we are familiar with the many different types of ataxia; spinocerebellar ataxias (SCAs), of which there have been more than 45 types identified, Friedreich’s ataxia, sporadic ataxia, to name a few. However, 30 years ago the only diagnoses available were idiopathic late onset cerebellar ataxia, Nonne-Pierre-Marie diease, or Friedreich’s ataxia. This really highlighted how far the field has come in the ability to diagnose people with a specific form of ataxia. Physiotherapy and speech therapy were described as the mainstays of treatment. Professor Timmann recommended that the more physiotherapy a patient is able to do, the better. Physiotherapy is also likely more effective when started early in the progression of the condition. Professor Timmann showed evidence that two weeks of postural training improved balance in the ataxias. Although there are currently no specific treatments for ataxia, Professor Timmann commented that this is an exciting time for the ataxia field, as genetic treatments are on the horizon. Professor Timmann also spoke briefly about a project she hopes to start working on soon, to study the role of the cerebellum in the processing of emotion. Pharmaceutical companies involved in the ataxias: An update In this session, Taylor Fields from IntraBio, and Dr Uwe Meya from Minoryx Therapeutics gave updates on clinical trials ongoing in their companies. IntraBio are developing therapies for neurodegenerative conditions, building on the expertise of their founding researchers from the University of Oxford and the University of Munich. The drug they are currently developing for ataxia is based on a chemical called N-Acetyl-Leucine. This chemical exists in two different forms, known as L and D enantiomers, and can also be administered as a mixture of L and D. IntraBio have shown that the L form is active in the mixture for the long-term treatment of neurodegenerative conditions. Therefore, they have made a medication containing only the L form (IB1001), to be tested in relieving the symptoms of ataxia. IB1001 is currently being tested in a number of neurodegenerative conditions, including ataxia-telangiectasia (AT). IntraBio hope to expand this to include cerebellar ataxia in the future. Minoryx Therapeutics are starting a Phase 2 trial of their compound MIN-102 in people with Friedreich’s ataxia. They have previously shown in cells that MIN-102 improves the function of mitochondria, which is compromised in FA. An initial study of this drug in control subjects showed good safety, and confirmed that the drug reached the brain. The phase 2 trial, in people with FA, started in April 2019 in a number of countries in Europe (Germany, Belgium, France and Spain).