Approximately 100 research scientists at the Montreal Neurological Institute for the third Symposium on ALS presented by the Fondation André-Delambre (October 4–5, 2007)

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease or Charcot’s disease, is a devastating, incurable disease characterized by a progressive loss of motor neurons, which gradually leads to paralysis and, in most cases, death from respiratory failure within a few years of diagnosis. On October 4 and 5, 2007, the Montreal Neurological Institute hosted the Fondation André-Delambre’s third annual Symposium on ALS.

Approximately 100 research scientists and clinical practitioners from various countries took part in the symposium to explore the causes of ALS, mechanisms of degeneration, experimental models and new therapeutic approaches currently in preclinical and clinical trials. Some 20 internationally renowned speakers from such institutions as CHU-Montpellier (France), Columbia University (New York), Emory University (Atlanta), Johns Hopkins University (Baltimore), Massachusetts General Hospital – Harvard (Boston), Methodist Neurological Institute (Houston), University of Alberta (Edmonton), University of Arkansas, University of California at San Diego, Université Laval (Quebec City), University of Toronto, McGill University, Université de Montréal, Umea University (Sweden) and University of Western Ontario were in attendance, at the invitation of symposium organizer Professor Jean-Pierre Julien.

The conference began with a presentation by Dr. Guy Rouleau (Université de Montréal) on the genetic causes of ALS. A major breakthrough was made in 1992 with the discovery of mutations in the gene for superoxide dismutase (SOD1) in about 20% of cases of familial ALS. Since this discovery, many research teams around the world have been trying to understand how SOD mutations can cause the selective loss of motor neurons. Dr. Rouleau also spoke about other gene mutations found in a few families with motor neuron diseases and, in some cases, of frontotemporal dementia. He addressed several technical and analytical problems linked to genetic and genomic studies for ALS. A great deal of effort is being expended on trying to identify predisposing genetic variations in cases of sporadic ALS. This is the classic needle-in-a-haystack scenario. Dr. Robert Brown identified a few recently discovered genes that may be associated with ALS, including angiogenin variants found in some cases of ALS documented in the United Kingdom as well as certain forms of paraoxonases, enzymes that play an antioxidizing role with respect to environmental toxins, which are risk factors associated with sporadic ALS. He maintained that some forms of paraoxonases could therefore increase susceptibility to environmental toxins.

The loss of motor neurons in ALS is not simply a problem intrinsic to motor neurons. It is also related to toxicity in the environment surrounding the neurons. An entire session was dedicated to discussing the role of glial cells in inflammation. Mouse model and cell culture studies presented by Dr. Don Cleveland (San Diego), Dr. Stanley Appel (Houston) and Dr. Serge Przedborski (New York) showed that mutant SOD1 proteins cause toxicity in microglia and astrocytes, which may lead to motor neuron degeneration. One of the hypotheses is that motor neurons are damaged by inflammation and lead to the overproduction of proinflammatory molecules, oxygen radicals and glutamate by gilial cells. However, more research is required to identify all of the toxic molecules secreted by the glial cells surrounding the motor neurons.

Thursday began with presentations on the abnormal properties of mutant SOD1 proteins (Dr. Stefan Marklund – Umea) and toxicity of mutant SOD1 proteins due to cell death signalling pathways, aggregation and alterations to the chaperone and protein degradation system (Dr. Heather Durham – McGill). Dr. Pierre Drapeau (Université de Montréal) updated us on genetic manipulation techniques on zebra fish that make it possible to use this animal as a model for neurodegenerative diseases, including juvenile ALS. Experiments with the zebra fish show results in a few days. Therefore, we expect that zebra fish studies will enable us to step up research on genetic factors involved in degenerative processes and test new therapeutic approaches more quickly. The first day of the symposium ended with talks on innovative in vivo imaging techniques. Dr. Jasna Kriz of Université Laval described a new bioluminescence imaging approach that can be applied to monitor the progress of ALS in mice in a non-invasive way and to assess the effects of experimental therapies. Finally, Dr. Sanjay Kalra (Edmonton) spoke about advances in magnetic resonance imaging in the tracking of the progress of ALS, particularly as regards an approach based on N-acetylaspartate/creatine ratios and a new approach known as diffusion tension imaging, which focuses on the diffusion of water molecules in tissue.

Friday morning started off with a presentation by Dr. William Camu on hypoxia and hyperactivity among ALS patients. He presented data suggesting that the tissues of ALS patients exhibited reduced oxygenation. Dr. John Crow continued with a talk on experimental drugs for ALS being tested on model mice. He reported that the antioxidant agent known as manganese porphyrin AEOL 10150 has proven to be one of the most efficient substances for slowing down the progression of the disease in model mice. Dr. Crow also discussed several compounds undergoing experimental tests, including neurotrophins, vitamin E derivatives and antiestrogens, such as . In addition, he addressed problems associated with mouse model studies. He was followed by Dr. Jonathan Glass (Atlanta), who spoke about the importance of axon protection in ALS. Experiments have shown that protecting nerve cell bodies is pointless if axons are absent from the system. It is therefore necessary to develop strategies for maintaining the integrity of axons in ALS patients.

A full session was dedicated to immunization approaches for the treatment of ALS. Dr. Jean-Pierre Julien showed that vaccination with a mutant SOD1 extended the life of ALS mice by approximately 10%. Moreover, he indicated that he had successfully tested a passive immunization approach that involved injecting specific antibodies to counteract mutant SOD1 proteins. His work is currently focused on characterizing monoclonal antibodies that will help neutralize the toxic effects of mutant SOD1. The idea is to “humanize” the most promising antibodies in order to develop an immunotherapeutic treatment in cases of familial ALS caused by SOD1 mutation. He reviewed results that support the idea that SOD1 anomalies can also contribute to the pathogenesis of sporadic ALS. The future of immunotherapy in the treatment of sporadic ALS is yet to be seen. Dr. Avijit Chakrabartty (University of Toronto) has also developed polyclonal antibodies in rabbits that are capable of recognizing mutant human SOD1 proteins, based on the observation that certain peptides become exposed in mutant SOD1. Dr. Janice Robertson presented her work on active vaccination in ALS mice using a mutant SOD1 and an SOD1 peptide. These results corroborate findings previously published by Dr. Jean-Pierre Julien and support the concept of immunization in the treatment of ALS caused by SOD1 mutations.

The symposium wrapped up with presentations on clinical issues. Dr. Jeffrey Rothstein spoke about the role of astrocytes, the screening of potentially neuroprotective compounds designed to increase the levels of GLT1 glutamate transporters and the latest advances on the experimental transplant of astrocyte progenitor cells for treatment purposes. Finally, Dr. Merit Cudkowicz presented updates on recent therapeutic targets and clinical trials. The design of clinical tests is vital. It must be carefully determined how many patients will participate in the study, select the appropriate dosage of medication to be used and determine the manner in which it is to be administered. She also touched on the failure of clinical trials using minocycline. At 400 mg per day, minocycline accelerated the progression of ALS in patients by 25%. The trials were therefore discontinued. It is unknown why the results were negative in humans, when minocycline had exhibited protective qualities in mouse models. Researchers have questioned the dosages used and new clinical studies using lower dosages may be resumed. A recent study, for example, showed that 200 mg of minocycline per day provides protection after cerebral ischemia. Several other compounds are also currently being assessed in clinical trials. The results of these studies will be made known in the coming years.

The third Symposium on ALS presented by the Fondation André-Delambre was a success not only in terms of turnout, but also because of the high level of scientific discussions, the enthusiasm shown by participants and the volume and quality of the findings of cutting-edge research presented by speakers. The event featured two days of intense debate on the latest ALS studies. What set this symposium apart was its relaxed atmosphere conducive to dialogue as well as its ability to bring scientists together and encourage them to join forces. We hope that these synergies will help advance research at an even faster pace and bring us closer to finding a therapeutic approach to eradicating this devastating disease.