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als: new therapies offer hope in treating a mysterious deadly disease
als expert dr. agessandro abrahao and his team conducted a world-first study using mri-guided ultrasound to open the blood-brain barrier so drugs can directly target the brain regions affected by amyotrophic lateral sclerosis.
apr 4 2023
6 minute read
dr. agessandro abrahao is a neurologist at the als clinic, sunnybrook health sciences centre, and assistant professor of medicine, university of toronto. he is on a mission to solve the mystery of als. supplied
everything your body does, feels and interprets is controlled by a kind of command centre, namely the brain. that three-pound mottled ball of tissue controls everything from thought to memory to emotion to vision to breathing to motor skills. and when that complex, vital little organ short-circuits somehow, when it falls down on its job and stops issuing these commands, bad things can happen to our body. one of those bad things is amyotrophic lateral sclerosis , or als (also known as lou gehrig’s disease), a neurodegenerative motor neuron disease that leads to paralysis.
over time, als causes muscles to break down and those living with the disease — about 3,000 canadians, according to the als society of canada — will lose the ability to walk, talk, eat, swallow and, eventually, breathe. roughly 80 per cent will die within two to five years of diagnosis. even worse? there is no cure, and the cause remains a mystery. but there are promising new treatments that can slow the decline and improve quality of life. the catch? not by much. at least not yet.
but researchers are working on it — more than 50 drugs are currently being studied. healthing caught up with dr. agessandro abrahao, a neurologist at toronto’s als clinic, which is housed in sunnybrook health sciences centre , and assistant professor of medicine at the university of toronto, to hear more about the progress in the treatment of this devastating disease.
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what therapeutics are currently used to treat als in canada?
there are three drugs approved in canada: riluzole is an oral medication that helps protect the motor system from neurotoxicity and slows the disease progression by about five to 10 per cent over time, with a survival benefit of around two to three months. edaravone, in a small clinical trial, was found to slow the progression of als by about 30 per cent in the earlier stages.
the third and most recent [approved in canada in june 2022] is sodium phenylbutyrate/taurursodiol, or pb-turso. the clinical trial that supported the preliminary approval was a small study that slowed progression by about 35 per cent in patients with early stage disease. it’s important to note that none of these drugs stop disease progression, or return any lost function. patients continue to decline, but at a slower rate.
can patients access these drugs easily, and are they expensive?
these drugs are extremely expensive and, in general, patients are only eligible for coverage in the earliest disease stages. at this time, only riluzole and edaravone are covered under the provincial formularies, and private insurance coverage is variable.
can all three be combined for better effect?
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each of these medications has a different target: riluzole targets a chemical disbalance that causes neurotoxicity; edaravone targets free radicals; and pb-turso helps the metabolism of the motor neurons. it appears that they can be used together safely. they’re part of the standard of care now.
how much more research is ongoing?
the number of clinical trials and research is thanks to a network that was formed in 2008 called cals, or the canadian als network, founded by my close colleague dr. lorne zinman, from the university of toronto. cals has also conducted collaborative research to better understand why people get als, how it progresses, and to identify disease markers that can be used to develop therapeutics.
why is als such a hard disease to treat?
we don’t have a complete understanding of the disease mechanisms to define the optimal therapeutic targets. also, promising therapeutics have limited access to the brain and spinal cord because of a protective layer called the blood-brain barrier, which works as a filter to prevent viruses, bacteria and toxins from getting to the brain. however, it also limits drug access to the regions of the central nervous system affected by als.
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at sunnybrook’s harquail centre for neuromodulation, we conducted a world-first study using a novel technology called mri-guided focused ultrasound to safely and reversibly open the blood-brain barrier. this non-invasive technique creates a therapeutic window whereby drugs can directly target the brain regions affected by als. we will soon start the next trial phase where we will couple this ultrasound with a novel therapeutic.
are there any updates on how als is caused, or why it’s 20 per cent more common in men and in military veterans?
that remains a mystery. in about 90 per cent of cases, called sporadic als, it typically starts in adulthood, and is slightly more common in males than females. we now have a better understanding of the genetic forms of als, which account for about 10 per cent of cases, and can run in families.
gene therapy trials are testing therapeutics to try to reduce the toxic effects of als genetic mutations. the drug tofersen, which is in the early stage of regulatory review, showed significant improvement in nerve damage biomarkers in patients with mutations in the sod1 gene. unfortunately, it treats only a fraction of the genetic forms of als, but additional gene therapy studies targeting other mutations are underway.
what are some other theories for how als is caused?
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there have been studies on possible environmental factors, i.e., exposure to heavy metals, chemicals or pesticides. the problem is that als remains a very rare disease and exposure to heavy metals or pesticides is quite common. so that in itself does not explain the causality of als. also, people living in the same household are usually exposed to the same environmental factors.
another theory is that als could be caused by a virus, and there are studies looking at that. but then you would expect that everyone living in the same household would be exposed to the same virus. it’s rare to see als happening in couples. we have identified a few mutations that can cause als but there are probably other genetic factors that put that individual at risk, and some environmental factors that haven’t been established as well.
stephen hawking is one of the more famous people to have had als, and he lived 50 years with the disease where most others die in two to five years. why is that?
als is a heterogeneous disease and patients often have a variable progression. for some it starts in the legs or arms, for others the throat muscles, so they can present with speech and swallowing changes. stephen hawking had a very slow variant of the disease, whereas others have a fast progression. he also chose to be put on a ventilator once he became completely paralyzed, which prolonged his life.
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the disease heterogeneity, along with the incomplete understanding of the mechanisms and the cause, have contributed to many negative clinical trials. there are probably different forms or variants of this disease that may have different biological mechanisms in the background.
at sunnybrook, we’re developing biomarkers that can better characterize motor neuron dysfunction and identify more homogenous groups of patients for clinical trials. these biomarkers measure responses to novel nerve testing techniques and magnetic pulses sent to the brain by transcranial magnetic stimulation. these studies are in collaboration with the university of alberta and an international consortium that includes countries in europe and asia.
our hope is to create better ways to track this disease in clinical trials. there is other research looking at the causes, and we’re also developing ways to enhance the delivery of the right drugs to the right place at the right amount. we want to use these model techniques to accelerate drug development and to one day stop this devastating disease.
robin roberts is a vancouver-based writer.
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