According to Health Canada, 1 in 12 Canadians has a rare disease, and two-thirds of them are children. Among hundreds of rare diseases are amyotrophic lateral sclerosis (ALS) and Parkinson’s disease (PD), as well as less well-known diseases such as Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS), Leigh Syndrome, and Primary Lateral Sclerosis (PLS). On Rare Disease Day, Feb. 28, The Neuro looks back at the progress that its researchers and clinical staff have made toward understanding rare neurological diseases and looks forward to a future that gives hope of finding new, effective treatments.
Over the last several years, The Neuro has focussed more attention on rare diseases, engaging more staff and resources to deal with an ever-increasing mass of genetic data and tests. As the first academic institution in the world to fully embrace Open Science, The Neuro aims to accelerate the pace of discovery and develop new treatments for currently untreatable brain diseases.
“We thought this genetic revolution would have two impacts: it would help in disease diagnosis and genetic counselling, and secondly, it would give us better insight into these diseases and lead to new drugs,” notes Dr. Bernard Brais, co-director of the Rare Neurological Diseases Group, a neuro-geneticist who arrived at The Neuro in 2011 as a specialist in rare diseases with founder effects in Quebec. “This is what we’re seeing today. I think it’s going to revolutionize the treatment of many rare neurogenetic diseases.”
Aiding this revolution is a technique to conduct genetic sequencing at a more rapid pace and at decreasing cost.
“Today we offer cutting-edge genetic diagnostics, which was not the case when I first arrived,” says Dr. Brais. “Five years ago, I might have asked to test one gene at a time for a patient with a muscular dystrophy. Three years ago, I would have asked for 40. Now I ask for 400. The cost is dropping constantly and soon we’ll ask for a patient’s entire genome.”
Breakthroughs are coming within reach. As evidence, Dr. Brais points to Spinraza, a drug that changes completely the progression of patients with spinal muscular atrophy (SMA). Spinraza was approved in the United States in 2016 and in Quebec last December for all SMA types.
“Some of the children born with SMA died within two years, but if treated with Spinraza early in life, they develop almost normally,” says Dr. Brais. “It’s a very specific drug, something designed based on a genetic understanding of the disease. There’s also evidence that it can help adult SMA patients. We are working to give access to this new drug at The Neuro very shortly.”
The Neuro is well prepared to pick up the challenge of administering Spinraza, which requires making a lumbar puncture so that the drug can be injected into the patient’s spinal canal.
“We have a long track record of this and have a first-rate radiology department to help,” notes Dr. Brais.
Drugs for treating rare disease are typically expensive. The annual cost of Spinraza is several hundred thousand dollars.
“It’s expensive because it’s the first drug in its class. It reflects the cost of more than ten years of development in a new chemistry and clinical trial design for a rare disease,” says Dr. Brais. “Quebec’s government health care has been generous in agreeing to pay for SMA types 1, 2 and 3. Quebec has a track record of wanting to ensure that we’re pro-active in treating rare diseases, not because more Quebeckers have such diseases but because certain rare diseases are more frequent in the province, though not SMA.”
For Dr. Brais and his colleagues, Spinraza serves as proof that a molecule can be designed to reach the brain and correct a genetic defect.
“Our quest is to find rare disease genes that allow for their diagnosis while also serving as the first step toward the discovery of treatments. We’ll also be using The Neuro’s new, powerful 7 Tesla magnetic resonance scanner to test animal models of rare diseases to see how they respond to drugs. We’re looking at imagery protocols and cellular responses to develop strategies to find biomarkers that show how animal models and humans respond to treatments. For example, my colleague, Edward Fon, who works on Parkinson’s disease, is developing a platform to screen molecules on induced pluripotent stem cells (IPSc).”
Another colleague, Eric Shoubridge, is using his expertise in mitochondria, the part of a cell that provides functional energy to the cell, to see how mitochondrial mutations might lead to rare diseases like Leigh Syndrome, an early onset and fatal neurodegenerative disease. Leigh Syndrome is genetically heterogeneous---there are 75 known genetic causes.
Shoubridge’s lab is studying several different genetic defects in Leigh Syndome, including a French-Canadian variant that is relatively homogeneous because it’s due to a founder effect.
In conjunction with the Tanenbaum-Lunenfeld Institute in Toronto, Shoubridge is concluding a major project to map the interaction of more than 100 mitochondrial proteins and their neighbouring proteins. A paper on the subject will be published this year.
“We’ve built the basic interaction map, putting proteins into functional units where we think they might interact with other proteins so we have some idea of their function. Next we’ll try to see whether mutations in these proteins might cause disease.”
The laboratory of The Neuro’s director, Dr. Guy Rouleau, has been in the forefront of discovering specific genes that underlie rare diseases. His lab is narrowing down the search for a specific gene that could be the cause of primary lateral sclerosis, a disease related to ALS. Unlike ALS, in which patients typically die within a few years of diagnosis, PLS patients experience motor degeneration in parts of their body over the course of many years. Doctors can easily misdiagnose PLS as ALS.
“It’s so rare that it’s difficult to get samples for analysis. But our recent progress leads us to be hopeful in reporting a previously unreported PLS genetic risk factor in the coming year,” says Dr. Patrick Dion, scientific manager of the Rouleau lab. “Moreover, cell models carrying the candidate genetic risk factor were recently set up through treating physicians and affected individuals, a step that will enable us to explore the impact of the genetic defect at the molecular level.”
The Rouleau lab has already identified two genes linked to a rare condition called hereditary sensory and autonomic neuropathy type II (HSAN2). The condition affects sensory nerve cells causing the loss of feeling of temperature, pain and vibration.
“These identified genes interact in a protein region that is unique to them,” explains Dr. Dion. “We’re working to explain how this interaction recruits a number of additional proteins with functions that are relevant to the sensory deficit observed in patients. The network of interacting proteins identified with this effort will provide clues to the unfolding of the pathogenicity.”
Such a network could help to identify avenues that one day could sidestep the chain of events leading to some of the sensory deficits associated with HSAN2.
The Neuro’s numerous specialized clinics cater to rare diseases by giving access to the latest genetic tests and engaging basic science researchers to work on some of the mutated genes causing rare forms of neurological disorders.
Research into Rare Genetic Disorder Gets a Boost from La Fondation des Jumelles Coudé
The Neuro is thankful to La Fondation des Jumelles Coudé, for their generous and loyal support of Dr. Guy Rouleau’s research into sensorimotor polyneuropathy.
Disease causing mutation found in French-Canadians
A team of Canadian scientists, including researchers at The Neuro has discovered the first French-Canadian founder mutation gene linked to synucleinopathies, a group of neurodegenerative diseases that includes Parkinson’s disease (PD), dementia with Lewy-Bodies (DLB) and multiple system atrophy (MSA).