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Friedreich’s Ataxia Society Ireland (FASI) website
Research and euro-Ataxia Conferences - Sept. 24/25, 2008
The Research Day was opened by the Minister for Health and Children, Mary Harney and we have received very positive feedback on the success of both days We benefitted from excellent press coverage with an article featuring some of our members included in The Irish Times Health Supplement on 23rd September, an interview with another member and an overview of the Conference on RTE News at 1.00 pm and 9.00 pm on 25th September and a photograph of our Chairman, Tom Kelleher with the Minister appeared in The Irish Times on 26th September.
Below is a summary of all presentations made at the Research and euro-Ataxia Conferences. We will be preparing a Newsletter for our members with an abridged version of salient points from the most relevant of these; if you would like a copy, please contact us with your address.
Report FASI-Ataxia UK Research Conf Sept 2008 (.doc 174kb)
Report from euroATAXIA conf Sept 2008 (.doc 175kb)
FASI AND ATAXIA UK RESEARCH CONFERENCE
25th September 2008
The Stillorgan Park Hotel, Co. Dublin, Ireland.
This conference was opened by Mary Harney, Irish Minister for Health and Children. It was an honor, she said, for Ireland to host this meeting bringing together scientists at the top of their field from around the world, and patient representatives, especially on this date, the 25th of September, which is also International Ataxia Awareness Day. She spoke of the surge of investment in research and supporting young scientists in Ireland, and the government’s increase in health expenditure, the fastest growth in healthcare spending in Europe, making now a time of hope and reassurance.
Official welcomes and introductions to the day’s events were given by Dr Raymond Murphy (FASI), and then Professor Barry Hunt (Ataxia UK).
MORNING SESSION: FRIEDREICH’S ATAXIA RESEARCH
The conference got under way with a talk by Professor Richard Festenstein (Imperial College, London, UK), who spoke about epigenetic research in Friedreich’s ataxia (FRDA) and how the work in his lab had led to the investigation of potential epigenetic therapies (N.B. epigenetics = things which indirectly affect inheritance but are not in the actual DNA code). In each cell in the body there is memory about which genes should be switched on or off and this may be triggered by certain proteins which wrap around the DNA in the cell’s nucleus and affect the readability of the gene. Genes which are densely wrapped in heterochromatin seem to be harder for the cell’s transcription machinery to get to, and so these genes are silenced or switched off. In FRDA the gene coding for the protein Frataxin is switched off resulting in reduced levels of this essential protein.
But how does the heterochromatin structure form? In order to form an organised, readable structure, DNA coils around histone proteins. These histones have residues sticking out of the structure (‘tails’) that can be modified by the addition of different chemicals which are attracted to the residue, affecting it in different ways, in some cases by ‘silencing’ the gene in the region. The position of the gene is also important in determining the effect of modification on the activity of the gene.
Research now aims to explore these modifiers further and look for ways to interfere with the process so that genes could be 'unsilenced '. However it will be important to check that the regulation of other genes is not adversely affected.
Work in FRDA cells has shown that there is increased methylation on one of the lysine residues on the tail of histone H3, but at different levels in cells from different patients. This raises the question of whether the epigenetic profile corresponds with the clinical features and the severity of the condition.
Professor Festenstein’s work is also concerned with pausing of the enzyme, RNA PolII, which 'reads' the DNA code when genes are activated. Professor Festenstein's group have shown that in normal people the RNA polII enzyme appears to be paused within the frataxin gene keeping the gene silent. The theory is that in normal people it is silent until it is activated at some point by releasing the RNAPolII from its paused state - but in those with FRDA it remains silent. This pausing is therefore an area of interest. Such RNA PolII pausing may be affected by epigenetic character and modifications (e.g. methylation or serine phosphorylation) so this further suggests that epigenotype (as compared to genotype) may play a significant role in FRDA.
The researchers have identified some compounds which may be potential treatments utilising this approach, and have received some money from the Medical Research Council to study these further. In particular, there are several compounds which will be tested in mouse models to test their efficacy and also importantly safety.
Dr Joel Gottesfeld's lab in La Jolla, California (USA), is also working on heterochromatin modifiers as a potential treatment for FRDA, and Dr Gottesfeld started his talk by referencing a paper published by Richard Festenstein's group in 2003 (Nature) as the inspiration. His own work in California has supported the theory that heterochromatin gene silencing occurs in FRDA. The interaction between the active form of the frataxin gene and the inactive (silenced) form is mediated by enzymes called histone deacetylases (HDAC). To see if targeting these enzymes would result in an increase in frataxin, the researchers tested various commercially available HDAC inhibitors and found only one that was slightly active on the frataxin gene (compound BML-210). However they were then able to study derivatives of this compound and identified a compound (4B) which is active at increasing levels of frataxin mRNA and frataxin protein in cells.
The next stage was to test the compound in a mouse model of FRDA, and they found that it was able to cross the blood brain barrier and enter the nervous system; it also inhibited HDAC in the brain. There are different classes of HDACs, based on whether they are zinc dependent or non-zinc dependent, and different HDAC inhibitors act on each of the different classes. It is important for research to identify which enzymes are the target, and this gives clues as to the desired chemical properties of the inhibitor. Chemical studies that his team has carried out have now suggested that the class 1 HDAC enzymes are the target for HDAC inhibitors which work on the frataxin gene, and they have identified HDAC3 as the primary target.
The pharmaceutical company Repligen is now working with the active HDAC inhibitors that have been identified, doing pharmacokinetic and toxicology studies to learn more and identify the most effective compounds. A library of derivatives that can be screened for potential treatments has been established, and toxicity studies are going well.
The next speaker was Dr Piyush Vyas from Indiana University (USA), where research is focusing on replacing the frataxin protein which is deficient in people with FRDA. A deficiency of frataxin is thought to lead to cell damage due to an increasing iron accumulation, decreasing essential iron-sulphur cluster proteins, and increasing oxidative stress, so replacing this protein in cells would be a desirable treatment.
In Indiana, they have cloned a special form of human frataxin called TAT-frataxin. The TAT-frataxin protein that is encoded by this gene passes easily through biological membranes. This ensures swift entry of the frataxin protein into the sick cells where it is required. Preliminary lab studies on TAT-frataxin showed it has favourable properties such as binding to iron atoms and was able to reduce cytotoxic stress when administered in cells. The next stage was to test in mouse models of FRDA, which also yielded positive results. Mice given TAT-frataxin twice a week had an increased survival time compared to untreated FRDA models and improved coordination. Activity of selected enzymes also improved.
As this approach involves introducing a protein into cells, it was asked whether the treatment would invoke a reaction from the immune system. Dr Vyas said that some response might be expected but the studies on mice had not yet suggested this would be too toxic. Additionally, as humans with FRDA do have very low residual levels of frataxin already, it is not a wholly new protein being introduced.
Dolores Cahill is Professor of Translational Science at University College, Dublin. Her presentation involved the profiling of the antibody repertoire or antibodies in FRDA against protein arrays. This work is based on research Professor Cahill was involved in at the Max Planck Institute in Berlin, building a huge library of approximately 10,000 proteins which occur in the brain.
Studying the antibodies in blood is important because during the course of disease, where cells are damaged, proteins are leaked out into the blood and may trigger the immune system to respond. The antibody response has been identified in a number of brain disorders and ataxias and the researchers now aim to study the antibody profile of FRDA patients to better understand the condition. So far they have identified a number of proteins which are found in people with FRDA but not in healthy controls, including some families of proteins which are known to be involved in other neurodegenerative conditions (e.g. overexpression of the catenin family of proteins is known to affect the outcome in Alzheimer’s disease). These proteins may be involved in the onset or the progress of the condition, or may be a consequence of the disease pathway. More needs to be learnt about these proteins as they may also point to therapeutic targets.
For the rest of the morning the talk turned to clinical trials in FRDA, beginning with an update on antioxidant trials from Professor Massimo Pandolfo (Hópital Erasme-Universite libréde Bruxelles, Belgium).
We know that in FRDA cells are vulnerable to damage from oxidative stress and therapies which can reduce or counteract oxidative stress reactions (i.e. antioxidants) have been proposed for use in FRDA for a long time. The chief contenders are derivatives of Coenzyme Q, a natural compound which is an antioxidant and a facilitator in the respiratory chain for energy production in the mitochondria. Idebenone is a synthetic derivative of Coenzyme Q10 that appears to have greater bioavailability than Coenzyme Q10; it is taken up by isolated mitochondria and incorporated into the respiratory chain, restoring energy production in Coenzyme Q10-deficient cells. A number of trials have already been carried out testing Idebenone in FRDA patients but these have mostly been small, open-label (not placebo-controlled) studies which showed some improvement in heart function but inconclusive effects on neurological symptoms. It is thought there may be a relationship between the dosage given and the benefits. In a phase 1a trial, idebenone was well tolerated after a single dose up to 75 mg/Kg and showed maximal absorption at around 55mg per kg. A subsequent phase 1 trial showed idebenone was well tolerated for a month at 55mg/kg per day, opening the way for a phase 2 study of placebo and three doses of idebenone. The phase 2 study confirmed the excellent tolerability of idebenone at all tested doses, and provided promising results indicating a possible efficacy for a number of secondary endpoints, both neurological (such as the International Cooperative Ataxia Rating Scale) and cardiac. A possible dose-response relationship emerged for several parameters, further supporting a possible efficacy of idebenone.
Two major phase III trials are now ongoing in Europe (MICONOS) and the US (IONIA), testing different doses of idebenone (3 doses in Europe and 2 in the US) against placebo in a large number of patients. The primary endpoint in these trials is the improvement in physical ataxia symptoms and function measured by the International Cooperative Ataxia Rating Scale (ICARS). Other effects of FRDA, including non-neurological effects, will be measured in secondary endpoints (e.g. heart wall thickness, heart function, exercise capacity). Most of the participants have already started on these trials and some have already completed the one-year MICONOS trial and the six-month IONIA trial. Patients who completed MICONOS have been offered to participate in an open-label 2-year extension study with the highest dose of idebenone (2250 mg/day for individuals weighing more than 45 Kg, 1125 mg/day for those less than 45 Kg).
Other Coenzyme Q derivatives being considered are MitoQ and EPI-A0001, but there is no news of current clinical trials. Other treatment approaches are also being looked at in trials around the world, including iron chelators (see next talk), PPAR agonists (e.g. pioglitazone), and frataxin up-regulation (e.g. rhuEPO). Other potential treatments aimed to increase frataxin levels, such as histone deacetylase inhibitors (HDACIs), are still in pre-clinical development. It is likely that a polytherapy approach to FRDA may emerge, where the progression of the disease is targeted with a range of treatments acting in different ways.
One of these possible approaches was addressed by Dr Arnold Munnich (Hópital Necker-Enfants-Malades, Paris, France), who is involved in the trial of Deferiprone, an iron chelator. The theory of using iron chelating agents stems from the observation that children with FRDA who were given oral iron supplements for anaemia became worse rather than showing improvement. It was suggested that frataxin protein may be crucial in transporting iron for heme synthesis a component of haemaglobin. So when excess iron is given it just accumulates further in the cells instead of getting to where it is needed. Indeed when MRI scans were conducted on patients with FRDA, an accumulation of iron could be seen in certain parts of the brain. A trial in humans was planned based on the concept that mild iron chelation therapy with existing medicines may re-distribute the uncontrolled iron. Deferiprone was selected as a medicine already used in humans (for blood disorders) which can cross the blood-brain barrier and remove mitochondrial iron, but leave essential iron stores untouched. Experiments in cells with fluorescence staining showed that deferiprone did move iron from the mitochondria to other places, resulting in restored activity of the mitochondria and increased oxygen consumption and energy production. The restoring of the mitochondria may suggest that if iron-chelation was given early enough iron-related cell damage could be prevented.
In a preliminary trial in humans given a low dose of deferiprone there was a measured decrease in iron deposition in the brain. There was some clinical benefit observed in the youngest patients, but there were also some serious (but reversible) side effects in patients taking higher doses, meaning future studies need to be carefully monitored. This also suggests that iron should not be removed from the system completely. A multicentre, placebo-controlled trial has now been designed to test deferiprone over a longer period of time and to measure for any true effect on the neurological symptoms of FRDA.
In order to carry out scientific trials, there must be a reliable way of measuring the degree of disability and recording any changes or improvements. This is especially important in FRDA because initial treatments which are being tested are unlikely to result in a dramatic improvement but may slow down the progression, which is difficult to measure. Professor Martin Delatycki (Murdoch Childrens Research Institute, Melbourne, Australia) spoke about work at his institute which tested clinical outcome measures in FRDA. They concentrated on two types: clinical neurological rating scales and vision/eye measurements.
Four different rating scales were assessed (ICARS, FARS, FIM and Modified Barthel Index) and found to have good validity; that is their results corresponded with the duration of the disorder in individuals tested and compared well with each other. The FARS had the most statistical significance, with the most practical group size (60 patients) needed to give good statistical power for a clinical trial, but there were some aspects of the FARS examination which were deemed not to be useful (e.g. absence of reflexes which may occur even before diagnosis).
Eye movements can be useful to measure, as in FRDA there is marked latency in saccadic movement (following with the eyes independent of head movement) and velocity, which generally becomes more marked with more severe ataxia. These movements can be measured objectively using the scleral coil technique or infra-red oculography. Research is ongoing to re-test patients over time and see if these techniques can reliably assess changes and could be used in trials.
AFTERNOON SESSION: RESEARCH INTO THE CEREBELLAR ATAXIAS
A fitting introduction to the afternoon’s topic was a talk by Professor Olaf Riess (University of Tubingen, Germany), on the EuroSCA program and associated scientific projects. One of the problems faced by researchers in the field of cerebellar ataxias is the huge variety of different genetic mutations and the different clinical picture that can occur in conditions all lumped together under spinocerebellar ataxia (SCA). In addition, the different SCAs have different frequencies in different countries and in some cases there may only be one or two affected people in the population. Therefore it is necessary for researchers and clinicians from different countries to work together and share their findings and experience. The EuroSCA project is an integrated project for scientists involved in research into SCAs. The project was awarded funding from the EU to work towards many objectives including establishing the world’s largest DNA registry for ataxias, collecting epidemiological data, identifying new genes and establishing mouse models for all the known SCAs.
The project has resulted in a registry of over 3000 patients, including data from over 30 large families with unknown SCA, and has led to increased definition of some of the loci that are associated with disease and a greater understanding of disease modifying genes. There are now also animal models available for SCA1, SCA2, SCA3, SCA6, SCA7, and SCA17. Ongoing research that is part of EuroSCA includes projects using crystals as models of disease and treatment studies testing rapamycin and potassium channel inhibitors in SCAs.
Dr Thomas Klockgether (University of Bonn, Germany) is clinical coordinator of EuroSCA, and he spoke about the clinical side of the project, which involves 17 centres from 10 European countries. The clinical objective was to establish the infrastructure to allow interventional trials in SCAs when they become possible. To achieve this, there are three arms: a registry of patients (which now has ~4000 patients); developing instruments for assessing patients; a natural history study.
For assessment, the researchers have developed the SARA scale based on the standard neurological examination used by neurologists, and the INAS (inventory of non-ataxia symptoms) count- a list of 16 symptoms that may occur in SCA. Amongst the findings of the natural history study is the observation that in SCA1, 2 and 3, disease severity depends quite precisely on the number of genetic repeats and the duration of disease, whereas in SCA6 the main determinant is age. The disease progression is fastest in SCA1 and slowest in SCA6.
Another way to measure health state is to use a questionnaire to assess the patient’s subjective experience. The EQ-5D is a generic questionnaire with questions concerning the patient’s quality of life and ability to carry out everyday activities to compare with other conditions or to monitor any changes. Testing in SCAs (SCA1, 2, 3, 6) showed that most patients had some problems with mobility and carrying out usual activities, but few problems with self care. A finding that is perhaps under-recognised by scientists and clinicians was pain/discomfort which occurred in many people with SCA.
Depression and anxiety were other factors which are not part of the typical clinical description of SCA but can have a major impact on a person’s quality of life. On a visual analogue scale used to measure quality of life the average score of people affected by SCA was comparable to average scores in FRDA, Parkinson’s disease, and epilepsy, other long-term conditions. Most significantly, a rise in score on the physical symptoms inventory (INAS) was associated with a 1 point drop in the quality of life scale, but depression caused a much bigger drop of 12 points on the same scale. Therefore it is very important for clinicians to look out for and manage symptoms of depression in ataxia patients.
Dr Matthew Wood (University of Oxford, UK) has been working on RNA therapy for SCA, in particular focusing on SCA7. This condition was chosen because the researchers have access to a large cohort of patients in South Africa, where SCA7 is particularly prevalent, and it causes a particular problem in the eye (retinal degeneration) which means treatment could tentatively be tested in the eye without exposing the central nervous system.
RNA could potentially be targeted in two ways; by modifying the mRNA processing and repair, or by silencing sections of RNA (RNA interference). Dr Wood’s work is looking at the latter technique.
SCA7 is one of a group of polyglutamine disorders which result from an abnormal CAG repeat in the affected gene leading to a toxic protein with an expanded polyglutamine tract. RNA is the mediating step where the polyglutamine gene is translated into a protein so if you can interfere with the RNA you can reduce the levels of toxic protein. The difficulty is that the specific part of RNA that is responsible for the mutant protein has to be targeted without affecting any of the other normal RNA. The CAG repeat expansion cannot be used as the target as everyone has some areas where this pattern of repeats occurs, so the researchers in Oxford have to look for specific single nucleotide point mutations (SNPs) which are specific to the DNA of a person with SCA7. This would have to be done for each individual to be treated with the RNA interference.
The researchers have succeeded in finding mutant-specific silencers which discriminate just against the protein mutated in SCA7, and in preliminary studies have shown that the appearance can be restored to that of a normal cell. They have now identified a compound which appears to be safe enough to take forward for tests in cells from patients and animal models.
After a break for tea, Dr Sylvia Krobitsch (Max-Planck Institute, Berlin, Germany) gave a talk about her research on the characterisation of ataxin-2. SCA2 is a late-onset spinocerebellar ataxia which is associated with mental deficits and occurs in 1-5 in 100,000 people. The condition causes loss of neurons of the cerebellum, and in the brainstem and substantia nigra- a part of the brain affected in Parkinson’s disease so that patients with Parkinsons-like signs may re-analysed for the SCA2 mutation. In contrast to the other SCAs neurodegeneration in SCA2 seems to be due to an abnormal concentration of the SCA2 gene product ataxin-2 inside the cell, rather than protein aggregations. The researchers in Dr Krobitsch’s lab aimed to identify the function of
ataxin-2 and explore the molecular pathways it affects.
The work has found that ataxin-2 has similar architecture to a yeast protein (Pbp1p) which has been extensively studied for its character and interactions with other proteins. This existing knowledge has been transferred to the human protein showing that ataxin-2 likely interacts in the same way, and that ataxin-2 is a component of stress granules, which appear when the cell is under stress (e.g. from oxidation or heat) and have a function in protecting the cell. The individual protein-protein interactions will now be studied further and this area explored as a potential drug target.
The final presentation of the day concerned a topic which has received a lot of interest in the media and the research world. Dr Alastair Wilkins is working on the potential uses of bone marrow-derived stem cells at the University of Bristol, UK, where stem cells are being investigated for various neurological conditions.
Stem cells are cells that are able to self-replicate and differentiate into different cell types. Bone marrow mesenchymal stem cells have been shown to differentiate into bone cells, fat cells and cartilage, and under certain situations may give rise to cells of the nervous system. This would make them a possible tool for repairing damage to the central nervous system, which normally cannot repair itself. Bone marrow cells have been chosen for investigation because of their favourable properties including being easily isolated and expanded, the versatile growth potential, migration to injured tissue, and the record of bone marrow transplants for other conditions which implies they are safe to use.
Stem cells may offer protection to the nerves in several ways; the cells may transdifferentiate into nerve cells to replace the damaged cells; provide nutrient support for the nerve cell; fuse with the damaged cell to prevent degeneration; or modulate the immune response. To test the ability of stem cells to protect nerve cells from degeneration the researchers caused stress to cells by depriving them of essential nutrients and found that the presence of stem cells prevented cell death, therefore they must be providing some of the nutrition support. They also found that stem cells appeared to offer protection to cells when they were exposed to stress from other means such as nitric oxide damage. Stem cells may play a role in signalling support pathways by secreting factors (e.g. brain-derived neurotrophic factor, BDNF) which encourage the growth and development of new nerve cells and connections, and promote survival of existing cells.
The ability of stem cells to fuse with other cells was discovered by studying post mortem brain tissue of women who had had bone marrow transplants from male donors. It was found that some of the women had male genetic material (Y chromosome) expressed in certain cells in their brains, implying that the transplanted cells had fused with their own cells. Furthermore, it has been observed that this phenomenon occurs with greater frequency in animals exposed to inflammation or irradiation, or in older animals, suggesting it may be a survival mechanism.
The next stage of the research is to test bone marrow-derived stem cells in mice models of degenerative ataxias and the researchers are about to commence studies in a FRDA model. Work is also ongoing to gain a greater understanding of cell fusion and whether cells can be engineered to produce beneficial support factors.
This report was written by Dr Laura Rooke (Research Officer, Ataxia UK)
euro-ATAXIA CONFERENCE and AGM
26th-27th September 2008
The Stillorgan Park Hotel, Co. Dublin, Ireland.
This year’s conference was hosted by the Friedreich’s Ataxia Society Ireland (FASI) and boasted a very full day of diverse talks covering a range of topics of interest to individuals and families affected by ataxia. A warm welcome and introduction to the event was given by FASI Chairperson Tom Kelleher.
MORNING SESSION: ATAXIA RESEARCH UPDATES
Professor Massimo Pandolfo (Hópital Erasme-Universite libré de Bruxelles, Belgium) began the day’s programme by talking about clinical trials. Trials are conducted when there is reason to believe that a treatment may improve some aspects of a condition, and is safe. Trial protocols are put in place to ensure we get fair and scientifically reliable evidence of the treatment’s effect, and to protect patients taking part.
Taking part in a trial can have benefits for patients, giving them a chance to take an active role in their treatment and access to the latest in research and medical care, but there are also risks involved. Ethical and scientific quality standards covering design, conduct, recording and reporting must be met by all trials help to keep patients safe.
Current trials being carried out in Friedreich’s ataxia (FRDA) are primarily trying to counteract the effects of reduced frataxin which occurs in those affected by the condition. The abnormality in FRDA appears to ‘switch off’ the frataxin gene, causing a deficiency of frataxin protein which appears to lead to decreased levels of essential iron-sulphur cluster proteins and increased damage to cells from oxidative stress. A major trial is underway looking at idebenone- a compound which may protect against oxidative stress. Smaller trials have already been carried out, showing a possible benefit on the cardiac condition associated with FRDA but inconclusive effects on the neurological symptoms. Large, placebo-controlled trials ongoing in Europe and in the US have almost completed the recruitment of patients and in some centres will begin processing the results shortly.
Other treatments being investigated are EPI A0001 from Edison pharmaceuticals, also targeting oxidative stress, an iron-chelating treatment (deferiprone), and pioglitazone, a drug proposed to work by activating mitochondrial DNA replication. There are also trials on treatments attempting to increase the level of frataxin protein (with rhuEPO), and at the preclinical stage (not yet in humans) investigations on treatments around the actual FRDA genetic fault. Professor Pandolfo commented that it is looking likely the future will see people with FRDA taking a range of treatments that act at different stages in the mechanism of the condition.
Dr Joel Gottesfeld’s work at the Scripps Research Institute (USA) looks at trying to overcome the silencing of the frataxin gene that occurs in FRDA. In recent years research has suggested that the silencing is linked to DNA being modified by repressive chromatin structures. DNA is normally wrapped around histone proteins to form nucleosomes. The histones have ‘tails’ which can make contact with adjacent nucleosomes, but these tails can also bind with enzymes and be modified to become active or inactive, for example acetylation of lysine makes the corresponding gene region inactive.
The acetylation reaction is controlled by histone deacetylase (HDAC), so molecules which inhibit HDAC may prevent this modification occurring in the frataxin gene and switch the gene back on. Researchers at the Scripps Institute tested a variety of available HDAC inhibitors and found one compound which was active on the frataxin gene. They then tested a derivative of this compound in a mouse model of FRDA and found that frataxin could be restored to normal levels.
These compounds are now entering the next stage, where their chemical properties and safety are being fully investigated to work towards testing in humans. The pharmaceutical company Repligen is carrying out this work, and has so far reported reasonable drug-like properties and safety in large animals. Meanwhile they have synthesised a large library of HDAC inhibitor derivatives that will be assessed in order to find the most effective compound to be developed into a drug. HDAC inhibitors are also being looked at for other conditions such as Huntington’s disease.
Professor Andrew Green is from the National Centre for Medical Genetics in Dublin. His talk went over the basics of genes and the genetic aspects of hereditary ataxias. Genes can be described as inherited elements which give a particular trait, or as sections of DNA which code for the construction of a particular protein. A person has two copies of each gene, one from each parent. Everyone has 30-40,000 genes in total, and 4-5 that are altered from how they were in our parents (due to spontaneous mutations).
Professor Greene’s centre in Dublin provides both genetic diagnostic and support services to families affected by genetic conditions. The support aspect is important because genetic tests significantly differ from other medical tests because of their deterministic nature, and the potential implications for relatives as well as the individual.
The ataxias may be inherited in different ways- some are recessive, meaning a person needs to inherit two copies of the gene to develop the condition (e.g. FRDA, AOA), some are dominant so only one gene is required (spinocerebellar ataxias (SCAs)). Another type of inheritance is X chromosome associated. Fragile X syndrome has been known as the second most common genetic cause of learning disability, and it has now been found that about 10% of intellectually normal male carriers of fragile X seem to develop an ataxia in later life.
Dr Thomas Klockgether (University of Bonn, Germany) is clinical coordinator of the EuroSCA project and gave everyone an update on this work. The project, which began in 2004 involves a collaboration between 17 different clinical centres in 10 countries working to improve scientific understanding of the SCAs and lay the groundwork for treatment trials. One of the outcomes has been a web-based registry that anonymously lists 400 people with SCA. This will help recruit patients to clinical trials.
Another outcome has been the development of new assessment tools to rate the severity of the condition, primarily the SARA scale. This is a scale which can be used by any neurologist and gives an objective measurement of symptoms. This is essential for consistency, so that information can be shared across different countries and doctors evaluating patients in different countries would get the same results.
Work has also been done measuring patient’s subjective view of their health. As expected most people (80%) with SCA reported problems with mobility, but a considerable number of patients also reported pain or discomfort, which are not usually recognised as symptoms of ataxic syndromes.
A study is continuing looking at the natural progression of SCAs over time. So far patients have been followed up over 12 months, with changes in their SARA score compared over the time. It has been shown that there is some variation in progression between different types of SCA, with a year seeing bigger changes in the SARA scale (an increase in severity of symptoms) with SCA1 and the least change (slowest progression) in people with SCA6. A number of promising drugs were identified as part of the EuroSCA project, which require further studies, including lithium for SCA1 and rapamycin for SCA3. Lithium has already been tested on a mouse model of SCA1 by researcher in the US and shown improvements in coordination, although the mechanism of action is unknown. Lithium is a drug commonly used in psychiatric disorders but there are safety concerns, as for example in high doses it can cause cerebellar damage. Because of these concerns a phase I (safety study) is taking place in patients with SCA1 in the US. Rapamycin is an immunosuppressive drug, which has been shown in cell studies to remove the toxic proteins present in SCA3. There are safety concerns over this drug too so researchers are now looking at derivatives of rapamycin. Another future plan is to carry out the RISCA study, which will monitor unaffected people from families known to carry SCA genes to learn more about the pre-symptomatic phase of the condition.
Professor Michel Koenig (Université Louis Pasteur de Strasbourg, France) gave an update on research into the recessive ataxias. These are conditions where the parents are not affected so may not be aware that they carry the disease gene and can pass it on to their child. As a group, the recessive ataxias tend to cause symptoms to start at an earlier age (e.g. under 30 years old) than the dominant ataxias. The disease occurs because a genetic mutation causes an abnormality in the protein produced by that gene and classification can be based on the original function of the protein, for instance: a protein located in the mitochondria or involved in protection against oxidative stress (e.g. FRDA, AVED, SANDO, IOSCA, ARCA2) or DNA repair (e.g. AT, ATLD, AOA1, AOA2, SCAN1). Another way to classify the conditions is by the site where degeneration occurs. Mitochondrial-related conditions tend to affect the spinal cord, whereas other types tend to affect the cerebellum only.
The most common of the recessive ataxias in Europe is FRDA, and ataxia with vitamin E deficiency is the second most frequent only in North Africa, due to the presence of a common founding mutation. Around 50% of those thought to be affected by a recessive ataxia still cannot be diagnosed. Serum markers detected by simple blood tests can be useful in diagnosis, for example in ataxia telangiectasia and AOA2 the level of alpha-fetoprotein (Éø-FP) in the blood is increased.
Professor Koenig finished his talk by describing a new form of recessive ataxia which has recently been identified. Autosomal Recessive Cerebellar Ataxia 2 (ARCA2) causes exercise intolerance, mild mental retardation and ataxia. The protein abnormality has been linked to a role in the synthesis of coenzyme Q10 (an antioxidant found mainly in the mitochondria) which means ARCA2 may be an exception to the rule concerning classification of recessive ataxias as it mainly affects the cerebellum, not the spinal cord.
To finish the morning, a fascinating talk was given by Dr Pierre Vankan (Santhera Pharmaceuticals, Switzerland), discussing his theory of the ice-age origin of the distribution of FRDA prevalence across Europe. As part of the preparation for clinical trials, Dr Vankan collected data on the numbers of people affected by FRDA from patient groups and clinicians in different countries. As he did so he began to notice an unusual distribution so he began looking for patterns across the map of Europe. A clear gradient emerged, with the greatest prevalence of FRDA in south western Europe (e.g. 1 in 20,000 people in parts of Spain) and the lowest prevalence in the north east (e.g. there is a prevalence of 1 in 100,000 in Norway, and records of only 7 affected patients in the whole of Finland). This gradient can even be seen in individual countries, such as in Germany where there is a much higher number of people with FRDA in the south west of the country.
The GAA repeat at the root of FRDA is thought to be the product of a virus infection in primates around 40 million years ago before the evolution of humans split completely away from other primates. As evidence for this, GAA repeats of around 3-4 can be seen in other primates. However the much longer, expanded mutation which causes FRDA is only found in caucasians, so must have come from one descendent after the caucasians had split from other races.
If you feel like reading an unputdownable novel while collaborating with a just and solidary cause, "The Legacy of Marie Schlau" is your book! 100% of all funds raised will be dedicated to medical research to find a cure for Friedreich's Ataxia, a neurodegenerative disease that affects mostly young people, shortening their life expectancy and confining them to a wheelchair.
The life of Marie Schlau, a German Jewish girl born in 1833 hides great unsolved mysteries: accidents, disappearances, enigmas, unknown diagnoses, disturbing murders, love, tenderness, greed, lies, death ... alternatively a different story unfolds every time and takes us closer to the present. Thus, there are two parallel stories unravelling, each in a different age and place, which surprisingly converge in a revelatory chapter.
Paperback and Kindle versions for "The legacy of Marie Schlau" available for sale at Amazon now!
Currently, BabelFAmily is financing two promising research projects aimed at finding a cure for Friedreich's Ataxia. Whenever you make a donation to us or purchase a copy of "The legacy of Marie Schlau", this is where all funds raised will be devoted to:
1) Gene Therapy for Friedreich's Ataxia research project:
The project is the result of an initiative of Spanish people affected by this rare disease who are grouped in GENEFA in collaboration with the Spanish Federation of Ataxias and the BabelFAmily. The Friedreich’s Ataxia Research Alliance (FARA), one of the main patients’ associations in the United States now joins the endeavour.
2) Frataxin delivery research project:
The associations of patients and families Babel Family and the Asociación Granadina de la Ataxia de Friedreich (ASOGAF) channel 80,000 euros of their donations (50% from each organisation) into a new 18-month project at the Institute for Research in Biomedicine (IRB Barcelona). The project specifically aims to complete a step necessary in order to move towards a future frataxin replacement therapy for the brain, where the reduction of this protein causes the most damage in patients with Friedreich’s Ataxia.
The study is headed by Ernest Giralt, head of the Peptides and Proteins Lab, who has many years of experience and is a recognised expert in peptide chemistry and new systems of through which to delivery drugs to the brain, such as peptide shuttles—molecules that have the capacity to carry the drug across the barrier that surrounds and protects the brain. Since the lab started its relation with these patients’ associations in 2013*, it has been developing another two projects into Friedrich’s Ataxia.