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Report on the International
Symposium, Milan,
November 2003 - (abstracted) Over the weekend of 15-16 November, researchers, clinicians and healthcare professionals from 32 countries started to congregate in Milan . Bemused locals wondered if these people knew that they were about a month too late for the Milan Fashion Week. However, over 700 delegates attending the 14th International Symposium on ALS/MND knew something that most of the locals didn't - that the Quark Hotel in Milan was THE place to be, to learn about the latest trends in ALS/MND care and research. The big question that everyone wants to know the answer to is why do people develop ALS/MND. In the opening presentation of the Symposium Dr. Ettori Beghi (Milan, Italy) described how population registries are a useful way of collecting information on and analysis of possible risk factors for ALS/MND. Dr. Beghi presented a challenge to neurologists planning clinical trials when he suggested that a more detailed understanding of the trial participants might give a truer picture of the effects of the drug under investigation. Qualitative research allows us "to explore the context of people's responses and the explanations for them," explained Dr. Jane Ritchie from National Centre for Social Research, UK at the beginning of her presentation. "We can look closely at people's individual circumstances and the underlying factors influencing their feelings and perspectives". This type of research is crucial to developing evidence on which to build the standards of care for people with ALS/MND. In conclusion, Dr. Ritchie encouraged delegates to consider the use of qualitative research in their work, to further knowledge in the field of ALS/MND and how it affects people's lives. Everybody needs good neighbors: Soon after the discovery that mutations (abnormalities) in the SOD1 gene caused a fifth of all cases of the rare, familial form of ALS/MND 10 years ago, researchers developed an animal model of ALS/MND, by incorporating the mutated human SOD1 gene into mice. These mice develop an adult onset motor neuron disease. In both mice and humans one of the conundrums of understanding this form of ALS/MND is why these mutations are only toxic to motor neurons, when they are present in every cell in the body. The latest research by Dr. Don Cleveland from California , USA presented at the Symposium went some way to answering these questions. Dr. Cleveland has bred mice that contain a random mixture of cells containing normal and mutated SOD1 respectively. He found that there was a large variation on the survival time in these mice. Animals with an equal mix of cells containing healthy and mutated forms of the SOD1 gene did not go on to develop ALS/MND. In other words the cells containing the normal SOD1 gene appear to rescue or protect the neighbouring motor neurons with the mutated gene. To his surprise Dr. Cleveland found that as little as 35% of the cells containing normal SOD1 gene can have a protective effect. However, these observed effects also have a down side. The presence of a few cells containing the damaged SOD1 gene can cause their healthy neighbouring motor neurons to degenerate. Thus he commented, "having good neighbours matters"! " This research has great therapeutic implications" Dr. Cleveland concluded, "The delivery of normal non-neuronal cells to spinal cords could be completely protective, without replacing a single neuron". Clinical trials: There was barely a seat left in the room for the clinical trials session, which was the scene of mixed emotions and controversy. The disappointing results of a creatine clinical trial presented in Melbourne 2002 were reinforced with the results of a further trial presented in Milan . "At 5g (per day) we could not determine a benefit of creatine in people with ALS/MND," concluded Dr. Jeremy Shefner from New York , USA representing the trial consortium. Hope : The rate that a drug is broken down by the body can affect its beneficial effects. A small percentage of people taking Riluzole break down the drug faster than average. Dr. Geert Groeneveld ( Utrecht , Netherlands ) presented a study investigating the effects of increasing the dose of Riluzole in this minority, to maintain the optimal concentration of the drug in the body. Although no serious adverse effects were observed, Dr. Groeneveld suggested that further study was needed before a higher dose of Riluzole could be routinely given. Principal investigator Dr. Paul Gordon described two studies that showed that the antibiotic minocycline was safe and well tolerated for up to eight months in people with ALS/MND. Following the success of these trials, plans for a Phase III study to investigate the beneficial effects of minocycline are underway. Delegates also heard from Dr. Ben Brooks, Madison USA who described how the possible beneficial effects of the breast cancer chemotherapy agent Tamoxifen came to light. Patients with a co-diagnosis of ALS/MND and breast cancer seemed to survive longer than those with the diagnosis of ALS/MND alone. Laboratory investigations suggested that Tamoxifen might be beneficial for people with ALS/MND. In preliminary results of an ongoing 12-month study, Dr. Brooks showed that Tamoxifen did not have any serious side effects in the 100 trial participants. Further results of this and future studies will confirm the very early indications of improvements in muscle strength and survival of people with ALS/MND. Controversy and surprise: Following the recent publication of her paper on a study to investigate the feasibility and safety of administering stem cells to people with ALS/MND, Dr. Mazzini gave an update on her research in this session of the Symposium. From the seven patients that have received stem cells to date Mazzini and colleagues concluded that "Our results appear to demonstrate that transplantation of these (stem) cells into the spinal cord of humans are safe and well tolerated by ALS patients". As in clinical studies of potential drugs, Dr. Mazzini used several standard tests for muscle strength and respiratory function to monitor progress during the study. Data from these measures up to 21 months after and 6 months prior to receiving additional stem cells were presented. All the patients are still alive, although both muscle strength and respiratory function are declining. One interpretation of the data is that the patients are declining at a slower rate after receiving the additional stem cells. In such a small group of patients, with no controls, it is difficult to say whether any differences in the rate of decline of muscle strength or in respiratory function would be due to the stem cell treatment or to the natural progression of the disease in these individuals. In addition to the clinical study, Dr. Mazzini briefly mentioned a study in progress in animal models of ALS/MND. Dr. Mazzini's presentation evoked some robust debate on both the methodology and ethics of conducting such controversial studies. These echoed Professor Michael Swash's caution in an editorial of the journal in which this study was published "it is inappropriate, in the present state of knowledge, to use stem cells as a therapy in ALS". In the closing session of the Symposium Dr. Lucie Bruijn, Science Director and Vice President of ALS Association, named three drugs that may be beneficial in ALS/MND. Promethazine, Ebselen and Cetriaxone were identified as a result of a large screening program in which 75% of the drugs licensed by the FDA were investigated. These drugs were found to have some beneficial effects in two or more laboratory assays and were studied further in SOD1 mice. These animal experiments are in progress and Dr. Bruijn commented that a report is being written for publication next year. Further information is available from the ALS Association website. Although two of these drugs are licensed for other indications in the UK , it should be stressed that these are very preliminary studies on their possible, beneficial effects for ALS/MND. Italian appreciation After expressing our appreciation for the evening's entertainer (an accompanied tenor) at the Symposium dinner, it was time to acknowledge the contribution of professionals that make a difference to people with ALS/MND. Dr. David Oliver, Palliative Care Consultant based at the Wisdom Hospice in Kent , UK was awarded the International Alliance of ALS/MND Association's Humanitarian Award. The award was given in recognition of his international educational role in the provision of palliative care in ALS/MND. The Award is supported by CINI, a member of the Alliance . Every year the contribution of an eminent neurologist who also runs an active research program is recognized by awarding the International Alliance Forbes Norris Award. This year the award was made to Dr. Bob Brown of Massachusetts General Hospital in Boston , USA . He is particularly known for encouraging international collaborations - many careers of well-respected North American and European researchers have been enhanced from a period as a visiting scientist in his laboratory. In light of this award it was fitting that Dr. Bob Brown had been invited to give the closing presentation of the Symposium. He started his upbeat talk by asserting, "We have 10 more therapeutic targets than we had 10 years ago". These include targeting other cells in addition to motor neurons. Dr. Brown also suggested that these drugs will probably involve "different agents acting in concert". One of the hurdles for developing drugs to treat ALS/MND is their adequate delivery into the brain and spinal cord. In the remainder of his talk Dr. Brown highlighted a number of new developments that could solve this problem. These included the potential of both gene and stem cell therapies respectively. "There is a sea change coming in ALS research," he concluded.
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