By Dr Julie Greenfield, Ataxia UK
A series of lay presentations were given by international ataxia researchers for the euro-ATAXIA conference. These are summarised below.
Update on recessive ataxias - Professor Michel Koenig (Strasbourg, France). Prof Michel Koenig from the University of Strasbourg began with an update on the non-Friedreich’s recessive ataxias and improving diagnosis. Screening to find the genes responsible for an individual’s ataxia is a difficult problem as there is no specific pathway linked to recessive ataxia. Rather, sensory nerve cells and nerve cells in the cerebellum are vulnerable in a number of different ways. He described next generation sequencing as a technological advance that will help in providing patients with specific diagnoses and highlighted how many new types of recessive ataxia are emerging, often very rare forms. Some newer conditions were described in some more detail. ARCA1, for example, is a pure ataxia only identified in Canada so far. He thought that the reason for not having identified other families is probably due to the technical difficult and high cost in finding mutations in this gene due to it being such a large size. ARCA2 is an ataxia associated with CoQ10 deficiency that could potentially respond to CoQ10 supplementation; and finally ARCA3 is a new entity which is associated with late onset, slow progression and a pure ataxia.
Can we manipulate our own stem cells and could this be a future therapy for the ataxias? Professor Silvia Marino (Barts and the London School of Medicine and Dentistry, UK).
Next Prof Silvia Marino spoke about the potential for using one’s own stems cells to repair the cerebellum in cerebellar ataxia. Her work to understand more about whether they can contribute to regeneration, how to control their quantity, and exactly how and where they can be activated, is ongoing. This work focuses on mice and on human cerebellum samples taken from people who are undergoing brain surgery. For more information see the Ataxia UK website as we are funding this project so a more detailed summary is available.
Exon skipping and gene silencing as potential genetic therapies for several spinocerebellar ataxias - Dr Willeke van-Roon-mom (Leiden University, The Netherlands).
Dr Willeke van Roon-Mom of Leiden University Medical Centre in the Netherlands has been trying to shorten the overly-expanded sequence of DNA that’s behind the toxic proteins found in some spinocerebellar ataxias. Her team has had encouraging results using a technique that causes the protein-making machinery skip over the toxic stretch of DNA in cells derived from people with SCA3. This project is funded by Ataxia UK and ADCA-VN.
Dominant ataxias update (Professor Thomas Klockgether, University of Bonn, Germany). Prof Thomas Klockgether from the German Centre for Neurodegenerative Diseases described some of the work of the European network of researchers euro-SCA. He explained that together they had developed an ataxia rating scale for use in trials (called SARA) that was now a well recognised tool used worldwide. They have been studying the clinical features and progression of the most common SCAs (ie: 1,2,3 and 6), and he told us about their search for ‘biomarkers’ that can be used to predict how the condition is likely to develop and be used in trials. In SCAs 1, 2 and 3 at least, brain imaging and the length of the ‘repeat expansion’ in the genes may prove reliable. He also described a study the European network is doing on relatives of people with SCAs. Lastly, he turned to trials in cerebellar ataxias and mentioned one that is ongoing at his Centre using aminopyridine (a drug used in multiple sclerosis). It has shown some encouraging results in a preliminary trial with 15 patients. It is not decided whether the company called Biogen will it take into larger trials. He also briefly referred to two other trials in cerebellar ataxia patients, one testing riluzole that is ongoing in Italy and another using varenicline for SCA3 (the smoking cessation drug) that has been performed in the US and showed only marginal effects.
An update on histone deacetylase inhibitors as potential therapeutic approach in Friedreich’s ataxia - Professor Joel Gottesfeld (Scripps Research Institute, US). Prof Joel Gottesfeld spoke about potential treatments for Friedreich’s ataxia (FA) known as histone deacetylase inhibitors (HDACi). Based at The Scripps Research Institute in California, his team investigates the precise way in which HDACi can increase levels of the crucial protein frataxin, which is much reduced in people with FA. Using this understanding they have been able to tweak HDACi molecules to improve their performance. He explained that one of these HDACi that they have developed with the pharmaceutical company Repligen is now being trialled in patients in a Centre in Turin, Italy. The trial started in March and involves 20 patients testing two different doses. No results are available yet. In the meantime his team are working on developing new molecules that have better properties and these will be back-up molecules. These will be taken to the FDA in the US soon in order to get ready for new trials.
Novel approaches towards developing therapies for FA – Dr Pierre Rustin (INSERM, Paris, France). Dr Rustin spoke about their recent research that highlights the importance of another pathway in the pathology of FA. Although we know that low levels of frataxin are a main cause of FA he explained that his team discovered that another protein called PIP5K is also involved. They found that the GAA repeat expansion in the FA gene that causes reduction in frataxin also causes reduction in a neighbouring gene called PIP5K. The reduction in PI5K has been shown in both skin fibroblasts and in blood cells of patients with FA. This protein is involved in keeping the correct structure of the cell which is important because if the structure is not correctly organised many aspects of life can be affected. Specifically this protein affects the actin cytoskeleton on the cell and this accounts at least for a part of the yet non-understood phenotype observed in frataxin-lacking cells, ie the actin network disorganisation. They now plan to study whether they can observe the same findings in nerve and heart cells. Dr Rustin explained that he felt that the current line of investigations and therapeutic approaches such as antioxidant therapy and the use of histone deacetylase inhibitors are still valid but we now have a better understanding of the complexity of the situation in FA and may point to additional targets too.
Update on idebenone trials in Friedreich’s ataxia - Dr Günther Metz, Santhera. Euro-ATAXIA’s lay talks closed with Dr Günther Metz of Santhera Pharmaceuticals and his summary of its development programme with the Friedreich’s ataxia drug idebenone. While the drug has been shown to be safe and well tolerated in clinical trials, the beneficial effect of idebenone seen in an earlier trial was not replicated later and thus results are currently inconclusive about how effective it is as a treatment. Data of an open label extension trial and a placebo controlled patient reported outcome trial are still awaited. Annual update on European Friedreich’s ataxia research consortium (EFACTS) - Professor Massimo Pandolfo (Université Libre de Bruxelles, Belgium).
Prof Massimo Pandolfo gave an update on the EFACTS study, the consortium of European researchers who are working towards treatments for Friedreich’s ataxia. It consists of 14 partners in Germany, UK, France, Italy, Belgium and he was pleased to announce the recent addition of Spain. They aim to recruit 600 patients with Friedreich’s ataxia and so far each Centre was exceeding their goals. They are aiming to get the infrastructure ready in order to be running well designed multi-Centre European trials in people with Friedreich’s ataxia as new potential drugs emerge. A number of basic science projects are also funded by EFACTS aiming to elucidate the structure and function of frataxin, produce useful cell models and discover new potential drug targets. An annual meeting was held 6 months ago and he was pleased to report that the external committee of evaluators gave very positive feedback on the progress of the project. Professor Pandolfo reported that there was just under 2 years left on the project and he emphasised the importance of thinking now about the future of this successful network. For this the support of patient support groups he felt was essential.