ALS takes away the patient’s motor functions one at a time, and the progress of finding effective drugs to counter its insidious effects has been slow. June is ALS Month, a good time to update the public on the latest developments in ALS research taking place at The Neuro.
The Montreal Neurological Institute and Hospital (The Neuro) is recognized as a leading Canadian centre for research into amyotrophic lateral sclerosis (ALS) as well as for its care of ALS patients.
Approximately 3,000 Canadian ALS patients are coping bravely with this debilitating neurological disease. Several hundred Canadians will be diagnosed with the disease each year.
In the past several years, The Neuro has intensified its research into ALS, giving rise finally to hope that effective treatments will be found to slow or perhaps even to stop progression of a disease that has so far largely defied medicine.
Important research is underway at The Neuro into the nature and causes of ALS. A $2-million donation by the Reed Family / The Tenaquip Foundation enabled The Neuro to establish the Reed Family Motor Neuron Disease Research Unit. The Neuro’s many national and international partnerships are helping to advance research into ALS and to develop effective treatments. Here are some of The Neuro’s ALS research projects:
Dr. Peter McPherson is investigating a protein known as C9ORF72.
“Mutations in the gene that encode C9ORF72 are by far the most common genetic cause of familial ALS, which is at the root of about one-in-ten cases of ALS,” says Dr. McPherson. “Mutations in this gene cause more genetic cases of ALS than all other ALS genes combined. People with this mutation tend to have parents and siblings with this mutation.”
Genetic mutations normally occur inside a gene’s coding sequence. But in the case of ALS, the mutation occurs outside the sequence. Dr. McPherson is looking to find the reason why.
“There are two competing theories. One theory proposes that the mutation in C9ORF72 causes a toxic sequence that ultimately prevents a variety of other cellular proteins from doing their normal functions. The other theory believes that the mutation leads to lower levels of C9ORF72 itself, which causes a form of cellular dysfunction that we are actively investigating”.
Dr. McPherson became interested in the C9ORF72 protein because it contains a module known as the DENN domain. The DENN domain’s function was discovered in his laboratory in a paper published in 2010.
“I had been working on DENN domain proteins for several years when I saw that the ALS disease gene had this protein module. It will certainly have an interesting function related to ALS.”
Dr. Gary Armstrong examines cellular defects in the early stages of ALS.
“We believe that by understanding the early defective changes in which spinal cord motor neurons communicate with muscles we can identify targets for therapy,” says Dr. Armstrong.
Dr. Armstrong’s laboratory uses a tiny aquatic vertebrate called zebrafish for conducting genetic, cellular and drug tests.
“We have established the methodology for generating zebrafish disease models that accurately replicate the genetic aetiology of ALS,” says Dr. Armstrong. “This allows us for the first time to generate the same genetic mutations in animal models so we can follow the disease progression and screen for compounds that might be developed as a therapy for ALS.”
Dr. Armstrong is part of a team that is conducting a clinical trial of Pimozide, a drug that was once used to treat schizophrenia but may protect motor neurons from dying in patients with ALS. In a small clinical trial, the drug appeared to slow the loss of muscular strength. A larger trial is in the works.
The ALS Society of Canada last year gave a grant of $2.2 million to researchers at McGill University, Université de Montréal and Laval University to use stem cell technology to investigate motor neurons and astrocytes in people with familial or spontaneous ALS. Grant recipients at The Neuro are Dr. Guy Rouleau, Dr. Patrick Dion, Dr. Edward Fon and Dr. Stefano Stifani.
The ALS clinic directed by Dr. Angela Genge is considered a model of multidisciplinary clinical care for ALS patients and their families. Employing advanced technology, the ALS clinical research program develops and tests new ALS therapies in collaboration with the Canadian ALS Clinical Trial Consortium (CALS), and with researchers abroad.
Several ALS clinical trials are underway.
“The Neuro is the only site in Canada to participate in a revolutionary drug study for a minority of ALS patients who are affected by the SOD1 genetic mutation, usually a cause of the familial form of ALS,” says Dr. Rami Massie, a neurologist at The Neuro involved in ALS clinical trials. “The ALS community is quite hopeful that this drug can significantly slow and perhaps even stop the disease progression for these patients. Our clinical trial subjects include patients from across Canada.”
– Examination of the effect of a new drug, Tirasemtiv, which aims to improve muscle strength and respiratory function.
– A study that examines the progression of multiple parameters in ALS patients in order to develop a reliable biomarker to help shorten the length of ALS drug studies. The parameters include respiratory function, muscle strength and electrophysiology. A biomarker would ultimately hasten new drug development and approval.
– A Canadian ALS Neuroimaging Consortium study that examines quantitative magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) in ALS patients, the study hopes that MRI data could also serve as a biomarker that could facilitate future research.
Dr. Gary Armstrong, a new principal investigator at The Neuro, is studying the cellular defects that occur in the early progression of ALS. His laboratory uses various methods — disease models with zebrafish, cellular assays and drug screening — to identify chemical compounds that might correct cellular defects. In the last year, he has revealed a new way to make zebrafish disease models, completed a study on synaptic defects, and was part of a team that finished a Phase 2 clinical trial with ALS patients.
Dr. Heather Durham has conducted ALS research for more than 25 years. Her laboratory seeks to understand why motor neurons become vulnerable to ALS damage and to find ways to boost defense mechanisms so that these neurons remain connected and function longer. Dr. Durham uses cell culture and mouse models that express genetic mutations causing the familial forms of ALS. A common abnormality in ALS that develops in motor neurons is retraction of processes called dendrites that connect to other spinal cord neurons and coordinate messages controlling movement. Recently, Dr. Durham’s laboratory identified underlying mechanisms regulating gene transcription that could contribute to those changes. Her group is testing drugs that target those mechanisms, both alone and in combination with other drugs that help cells deal with toxic proteins. Dr. Durham is a member of the ALS Society of Canada board of directors. She actively promotes ALS research and raises public awareness about the disease.
Dr. Angela Genge is a neurologist and director of The Neuro’s ALS Clinical Research Program, which handles about 300 patients annually. She is also director of The Neuro’s Clinical Research Unit, where trials of four ALS drugs are being undertaken involving about 50 patients. Dr. Genge has conducted research into the possibility that ALS might be linked to certain activities such as football.
Dr. Heidi McBride specializes in the biology of mitochondria, which are cell organelles that break down sugar and fat to generate energy. Her work looks at how mitochondria are regulated in both healthy and diseased organisms. Her research also looks to explain how the cell clears itself of damaged mitochondria. Dr. McBride aims to demonstrate how mitochondrial dysfunction might contribute to ALS onset.
Dr. Rami Massie, a neurologist at the ALS clinic, provides clinical care to patients from the moment of diagnosis to end-of-life care. His research activity in ALS focuses mainly on active involvement in clinical trials.
Dr. Peter McPherson uses molecular, structural and cellular techniques to conduct research into the function of nerve cell proteins. He has shown how certain proteins appear to contribute to neurodegenerative and motor neuron diseases. He has demonstrated in a mouse model how one protein, Scyl1, which helps to transport other nerve cell proteins, can undergo mutations that generate motor neuron degeneration similar to ALS in humans. Dr. McPherson also works on DENN domain protein models. One such protein is the product of the most common ALS mutation, the C9orf72 gene. In the past year he has identified new binding partners for the C9orf72 protein, providing a new functional role for C9orf72 in the function of lysosomes. Lysosomes are cellular organelles that control the quality of proteins and are a locus for responding to cellular stress such as in ALS. He continues to dissect the function of C9orf72 in cellular models including neurons derived from pluripotent stem cells generated from skin cells taken from ALS patients.
Dr. Guy Rouleau, Director of the Montreal Neurological Institute, was a member of a team that identified the first ALS gene in the 1990s. His laboratory at The Neuro studies ALS genes to determine the causes of both familial and sporadic ALS. Dr. Rouleau and his laboratory colleagues are looking at possible somatic mutations of cells in ALS genes that are known to lead to the outbreak of the disease. The laboratory’s activity includes making blood tests of people who either show ALS symptoms or are members of families with a history of ALS. The DNA from the blood is studied in an attempt to identify new causative genes.
Dr. Eric Shoubridge uses his expertise in mitochondrial biology to study the first identified gene in ALS encoding a mitochondrial protein, CHCHD10.
Dr. Stefano Stifani seeks to understand how vital motor circuits, including those controlling breathing, are assembled during development. The information that his laboratory uncovers can be used to generate motor neurons, as well as non-neuronal (glial) cells that are also part of functional motor networks, from pluripotent stem/progenitor cells obtained from ALS patients or from healthy individuals for comparison. Such generated neurons and glia open the road to a closer examination of motor neuron circuit pathophysiology in ALS and in other motor neuron diseases. Such cells can also be used in mass screening of potential therapeutic compounds, possibly leading to the development of new ways to maintain or even to repair damaged motor functions.
Dr. Hiroshi Tsuda examines genetic pathways and molecular mechanisms that underlie ALS. His research seeks to develop new therapeutics that could delay the onset and progression of ALS. His laboratory has created models that resemble phenotypes linked to ALS.
ALS in brief
Amyotrophic lateral sclerosis, commonly called Lou Gehrig’s disease after the baseball player who died of it, occurs as a result of the death of motor nerve cells in the brain and spinal cord. These cells control our voluntary movements. As more of these cells die, muscles weaken to the point of total paralysis. Death typically occurs less than five years following diagnosis, but a small percentage of patients live for ten years or even longer. Fewer than one in ten ALS patients has a family history of ALS. There is no cure.
June 8, 2017