Euro-ataxia Annual Conference 2016 Euro-ataxia held the latest annual meeting on 20-22nd May 2016 in Switzerland, hosted by the Swiss association Schweizerische Muskelgesellschaft! and organised by Ataxia UK. Ataxia UK’s Research Manager, Julie Greenfield, reports on the meeting: We were delighted that seventeen ataxia patient groups attended from European organisations, and in addition we were joined by charities outside Europe such as FARA-US and a new SCA3 charity in Israel. Five researchers from universities around Europe and two representatives from pharmaceutical companies also attended, making it a very interesting meeting with a variety of stakeholders but all with the common aim of finding treatments and improving the healthcare of people with ataxia. A whole day was dedicated to research updates and we are very grateful to the researchers who attended and gave interesting presentations (see summaries below). The Euro-ataxia business meeting took place the following day and we were pleased to welcome two new members to Euro-ataxia thus increasing our membership to 19 organisations. Patient registries A separate meeting was held prior to the Euro-ataxia meeting and this involved a discussion on the potential creation of a global patient registry, run by ataxia patient groups. Jen Farmer from FARA gave an overview and explanation of different types of registries, those including data entered by patients and those in which clinicians entered data with the latter often including more medical information and sometimes natural history studies. The focus of this meeting was on registries with patient reported data. An overview of current registries that are in existence was given and this was followed by a discussion on the potential creation of a global registry for Friedreich’s ataxia and also potentially one for other ataxias. A working party is being set up to progress this project. Research updates Dr Paola Giunti (University College London, UK) ‘Update on research activities at Ataxia Centre in London – dominant and recessive ataxias’ Dr Paola Giunti updated us on the many research activities at the London Ataxia Centre covering a wide range of ataxias. She has been part of the EuroSCA project, a European study on the more common spinocerebellar ataxias in which data for over 600 patients has been collected. Ataxia patients have been seen over an 8-year period and data collected on how their condition progresses, information of great importance when it comes to designing clinical trials. The London group have also studies cognition, as it is now known that the cerebellum not only controls movements but also has a role in cognition. Their results found that SCA6 is the slowest progression both in terms of ataxia rating scale and cognition. She also reported on a study on SCA1 on the effect of interruptions in the CAG repeats. They found that when the CAG repeats are interrupted it has an effect on the age of onset of the condition. Thus this information can be of help during genetic counselling sessions with patients. Dr Giunti has also been working on a project in FA in which they studied urinary, bowel and sexual dysfunction symptoms and a paper is due out soon on this work. A condition with some similarities to FA is ARSACS and a clinical study is ongoing in the London Centre. They have been measuring the thickness of the retina in the eyes of people with ARSACS with a simple technique called OCT. They found there is an increased thickness in the retina. This has now been shown to be a specific characteristic of ARSACS. Prof Massimo Pandolfo (Universite’ Libre de Bruxelle, Belgium) ‘Update on the development of biomarkers in Friedreich’s ataxia’ Professor Pandolfo described some of the latest studies that are attempting to develop good biomarkers for use in testing the efficacy of treatments in FA trials. A number of brain imaging studies are ongoing. Magnetoencephalography is a technique that detects a magnetic field given out by electrical signals from the brain. The use of this method in FA found that the signals generated by a tactile stimulus (somatosensory evoked responses) were delayed and smaller in FA compared to controls, thus he suggested this needed further follow-up as a potential biomarker of sensory loss in FA. MEG can also be used to measure brain signals in response to a movement (eg: in a finger or toe), which have been shown to be “coherent”, meaning they have overlapping frequencies. This phenomenon depends on proprioception, the sensation of position and movement of body parts, which is known to be altered in FA. In FA they found that this measurement is altered, and loss of coherence seems to correlate with the duration of disease. This requires multi-centre studies to confirm the results and see if it is of value as a biomarker. Prof Thomas Klockgether (University of Bonn) ‘Research update on sporadic ataxias, including MSA cerebellar form’ Professor Klockgether gave an update on non-inherited ataxias. He explained about the variety of different types of ataxias, such as acquired ataxias, (eg: caused by alcohol, medications), vitamin deficiencies (ie: treatable forms), infections causing ataxia etc. Immune mediated ataxias are also a large group of conditions. For example paraneoplastic degeneration (PCD) are ataxias which are caused by tumours, can be detected by antibodies, and where often the ataxia often occurs before knowing about the tumour. Diagnosis is very important as there is treatment, such as treatment of the tumour per se, plus immunotherapies. These conditions are rare so there have as yet not been any trials, but these therapies do seem to help patients. MSA cerebellar form is also a non inherited form of ataxia. It has a very defined neuropathology so a specific diagnosis can be given when people die. However, there are a number of features that help in diagnosis of patients during their life too. Prof Klockgether did a natural history study and confirmed that progression is normally more rapid than in other ataxias. He did however explain that there is some interest form pharma to develop a vaccination approach, bringing some hope for this condition. Indeed a trial is due to start soon in France. Some patients fall into the category known as sporadic adult onset ataxia, and these patients tend to have very slow progression. In some cases it has been possible via next generation sequencing approaches to identify genetic cause (eg: in one study he found that 20% of these patients actually had genetic causes that had been previously been undetected). He thus predicted that many of these patients might actually have recessively inherited ataxias. Prof Klockgether highlighted the potential benefit of symptomatic approaches for many of these ataxias, provided by drugs that might relieve ataxia symptoms rather than stopping the progression. One example is the riluzole trial (see next presentation). His group did a small open label trial of chlorozaxazone, a drug marketed as a muscle relaxant in Sweden, following a positive report. However, their trial in 17 people did not show any benefits. Similarly, a trial they did with 4 aminopyridine had no positive effects. In contrast, they found positive results of acetyl DL leucine in an open label trial so they are now doing a phase III trial. ESMI project Professor Klockgether also gave an update on a newly funded European multi-centre project in SCA3. This has received funding of 1.6M euros from the JPND as a 3-year project. They plan to bring together patients from a number of existing databases around the world to create one with over 700 patients. The project involves seven centres from European countries (Germany, UK, Portugal and the Netherlands) plus some associated centres from outside Europe (eg: Brazil, US). They plan to create a database with brain imaging scans, standardised clinical assessments and blood samples and will carry out a natural history study to assess how the condition progresses over the years. This information will be helpful in designing clinical trials to assess treatments. The researchers are keen for more Centres to take part in the project. A Steering Committee has been established and a patient group advocate from Euro-ataxia was invited to attend (Julie Greenfield, Ataxia UK). Dr Giulia Coarelli (Universita’ di Roma, Sapienza) ‘Riluzole as a potential treatment for the ataxias’ Dr Coarelli presented data from the two Riluzole trials they have conducted in a group of ataxias, the results of which are now published. This drug is marketed for another neurological condition, ALS, and is quite expensive. The most recent trial was a multi-centre randomised controlled trial in three centres in Rome. It included 40 people with different spinocerebellar ataxias and 20 with FA. There was a significant difference in the primary endpoint (SARA score) when comparing treated versus placebo after the 12 months. The results appeared less positive for FA than the SCAs. The results were encouraging, but she suggested that there should be further trials from other groups and reported that there might be a trial in Paris due to start on the spinocerebellar ataxias. Dr Isabelle Husson (Pediatric Hospital Robert Debré, Paris) ‘Studies on fatigue, physiotherapy and psychotherapy in young people with Friedreich’s ataxia’ Dr Husson from Paris gave an overview of her work with children and young people with FA. She has been following patients for a few years and has been doing a natural history study on 60 people with FA ranging from 6 years of age to 25. She highlighted the importance of muscle strengthening exercises and stretching as part of a physiotherapy programme, as this can work and can lead to improvements. This can have both a very positive psychological effect, especially for people with an otherwise progressive condition. In addition, it can have practical benefits because increased muscle strength in legs can help to improve gait, posture, and autonomy. For example it can improve the quality and security of transfers, ability to get dressed alone (especially shoes, socks, pants). In addition, these rehabilitation choices may decrease fatigue, and improve body image with nice psychological effects. Muscle strengthening exercises, stretching, and aerobic exercises, may be possible for patients, even if they are in wheelchair or use rollator. They can perform this rehabilitation with adaptation for each patient, taking into account their progress. Note that Dr Husson insists on the importance of active verticalisation that is also a strengthening and stretching exercises for leg muscles. She insists on independent rehabilitation and adapted sports for aerobic and strength improvement, as this can also have a psychological and social effect. Aerobic and endurance exercises are important. This importance is illustrated with a video of a young girl. Her gait was much better before muscle fatigue in the first meters of walking compared with after fatigue due to 200m. With better endurance, the gait quality will be better on distance. Another important area is the use of foot orthoses, orthopaedic shoes, or ankle brace, to prevent falls, ankle sprains and foot pain. In association with stretching and strengthening, they can improve gait and posture, stability and autonomy. Dr Husson focused on the importance of the rollator choice when it's necessary (too many falls, poor gait and posture stability, poor gait perimeter, social isolation etc). In her experience, it is important to choose an anterior rollator with forearm supports (better position, high comfort and stability, low fatigue due to the high stability). The use of rollator can postpone significantly the loss of walking ability. Combined use of a wheelchair or rollator depending on circumstances is possible, and it helps in terms of autonomy and quality of life. Using videos was a good way of showing the improvement to patients who may be reluctant to wear such foot orthoses, or to use a rollator. Again, a case study was presented showing clear improvements in walking in a girl after wearing orthoses and after using a rollator with forearm supports. The importance of a psychologist for acceptance of assistive devices is here totally clear. The goal is to avoid a progressive decrease of activities and socialization. A large percentage (69%) of her young patients with FA have urinary symptoms such as urgency and urge urinary incontinence, which can have huge psychological impact, especially in teenagers. She has been testing transcutaneous tibial nerve stimulation for overactive bladder, and positive results were seen in 3 patients, hence a larger study will now be done. Scoliosis was found in 86% of her young patients. Braces had been used as a treatment in nearly a third of these, which can be helpful in reducing back pain, improve posture and gait and reduce fatigue. A study is beginning also on this topic. Dr Husson finally reflected on how a psychologist should have a major role in supporting the young patient and their family in accepting the diagnosis, adapting to adjustments needed to daily perspectives and to restoring trust in their own capacities. A study on fatigue run by the psychologist is ongoing. Dr Jina Swartz (Takeda Development Centre Europe Ltd, UK) ‘D-amino acid oxidase inhibitor in the symptomatic treatment of cerebellar ataxia’ Dr Jina Swartz from Takeda gave a talk on a drug that her company are pursuing as a symptomatic treatment for the ataxias. Their drug targets the nerve cells in the cerebellum and it aims to increase levels of an amino acid called D-serine, which is thought to increase the activities of nerve cells and hopefully relieve symptoms of ataxia. At the moment they have done various animal studies to see if the drug has an effect. This has been promising enough to move to testing the safety of the drug in humans. The human study has started and they have given the drug to several dozen people (without ataxia) to date. If this phase I trial goes well the plan would be to do trials in people with ataxia. It is encouraging that Takeda are investing in ataxia research and are in the process of testing the effect of a drug that, although not a cure, could relieve ataxia symptoms in a range of ataxias. We have been working in partnership with Takeda for some time and we were delighted Jina Swartz was able to attend this meeting and inform patient groups across the world abut Takeda’s programme. Dr Robert L. De Jager (Retrotope Inc. USA) ‘A randomized, double-blind, controlled study to assess safety, tolerability and pharmacokinetics of RT001 in patients with Friedreich’s ataxia’ Dr Robert Jaeger from Retrotope described his company’s programme on the development of deuterated polyunsaturated fatty acids for the treatment of Friedreich’s ataxia. These are modified versions of the naturally occurring linoleic acid that people take in as part of a normal diet. Retrotope announced the opening of the first trial using this drug at the research conference we held in March 2015. More information on this research can be found in Ataxia magazine 190. Now Dr Jaeger reported that the trial is ongoing in the US testing two doses of the drug for 28 days in 18 people with FA. All participants have been enrolled and the drug appears to be safe. They are hoping to have some initial results on efficacy in the summer. The study has now also been extended to 6 months as a placebo controlled trial. This approach could potentially be of benefit to other conditions, such as other ataxias, in which oxidative stress occurs.