research and discovery transforming life with multiple sclerosis
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ms is an inflammatory disease “that rips the insulation off the central nervous system wires so that they don't conduct normally,” dr. mark freedman says, so replacing the immune system can stop progression.
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dr. mark freedman has patients who can walk and aren’t faced with a future of mobility issues. he’s a leading neurologist with the ottawa hospital research institute who heads up research and treatment for people living with multiple sclerosis (ms), long regarded as a silent disease because the disease advances even during remission.
ms is a chronic autoimmune disorder that affects the central nervous system, disrupting communication between the brain and the body, leading to physical and cognitive symptoms that get progressively worse.
only about 10 to 20 per cent of people with ms eventually need a wheelchair for full-time mobility, which reflects the development of disease-modifying therapies. but dr. freedman and his colleagues have gone a step further to improve lives for certain patients, even seeing one young man walk again after relying on a wheelchair.
how is that possible?
he had a bone marrow transplant to replace his dysfunctional immune system with new immune cells.
ms is driven by inflammation
ms is an inflammatory disease “that rips the insulation off the central nervous system wires so that they don’t conduct normally,” dr. freedman says, so replacing the immune system can stop progression.
“the insulation is essentially myelin and the myelin that is used in the central nervous system is different than, say, in your nerves and your arms and your hands. so it’s very exclusive to the central nervous system. now we are trying to figure out ways to prevent that, stop it, reduce it. and we’re still in quandary with trying to find something that will encourage the remyelination, like taping up the wire, that’s effective.”
there’s been success in this pursuit in mice, but researchers are searching for a therapy for humans to repair myelin or act as a neuroprotectant to prevent further damage from inflammation. “if we found a neuroprotectant, it would have real implications for many other conditions, stroke, obviously, and things like that. so, we’re still very much in need of that.”
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success of bone marrow stem cell transplant
but for patients who are young and early in disease progression, dr. freedman’s clinic has performed bone marrow stem cell transplants to replace their faulty immune systems. the team has worked with about 130 patients from across canada and followed an initial group of transplant patients for 25 years to monitor progress.
while many experts originally thought ms was a genetic disease, they’ve been proven wrong.
“there are genetics that definitely confer susceptibility,” says dr. freedman of the onset of ms. “but genetics are not running the disease. the immune system is because if you replace it and then the new cells regrow, the new cells are tolerant. they’re no longer attacking central nervous system myelin. none of those patients are on any drugs for ms. they’ve never needed another drug.”
patients who are further along in the disease have scar tissue and damage that can’t be repaired, so they aren’t candidates for the transplant.
but who knows what the future holds with scientific discovery?
dr. freedman’s career has shaped groundbreaking treatments, sparked by collaboration with researchers in other areas like cancer. the idea for a bone marrow transplant came from similar procedures for special cases of leukemia, especially lymphoma like hodgkin lymphoma, where cancer drugs were used to eradicate the malignant immune system and then a bone marrow transplant would offer functioning immunity, he explains.
“they would grab stem cells from the bone marrow and then replace the immune system and encourage the system to regrow, and then it’s no longer cancerous. that’s what they were doing for cancer cases. but why couldn’t we do that for autoimmune disease?”
one patient of the hospital’s ms clinic, geneviève bétournay of ottawa, had vision problems in her early 20s and then experienced her foot dropping, so she would need to drag it to move. her symptoms were caused by either a brain tumour or ms. an mri confirmed it was ms. through dr. freeman, her eventual stem cell transplant helped her turn her life around and she now runs art house, a popular coffee bar and gallery.
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as dr. freedman points out, the transplant has risks and consequences, including infertility from the harsh oncology drugs. there are weighty decisions to make, though patients like bétournay have decided to have eggs harvested and sperm banked for later use.
“i just saw one of the patients yesterday. she was in and she’s got a lovely little boy now. he’s about 12 years old,” he says. “she went through the transplant, waited a year or two for full recovery, and then once everything was back on track, they used in vitro fertilization with her husband’s sperm, so she could grow the baby and deliver it naturally. so we’ve had success and because it’s the young folks that unfortunately can have the most aggressive course [of ms], they’re the ones that you want to get early before they’re disabled.”
drug therapy controls early inflammation
while there is still much to solve in ms, there is a range of effective medications to control inflammation early in the disease. there are very few therapies, however, that help patients once they go on to the progressive course of the disease.
according to ms canada, about 85 to 90 per cent of patients initially are diagnosed with relapsing-remitting ms, where people experience symptom flare-ups for a period and then go for periods almost symptom-free. these patients may transition to secondary-progressive ms, where symptoms may not be as dramatic in variations, but there is a slow, steady progression. approximately 10 per cent of the ms population is diagnosed with primary-progressive ms, characterized by a steady worsening of symptoms from the start, without periodic relapses and remissions.
“once patients go onto that progressive course, that really can get in the brain and do something. like so many other diseases, if you can intercede early enough before chronic damage occurs, then you can control it,” notes dr. freedman.
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“think of heart disease. once you destroy the heart muscle because you’ve let too many heart attacks occur, you need a new heart. well, in the nervous system, it’s not easy to do a brain transplant. we can do a heart transplant, we can’t do a brain transplant. so you really want to prevent the damage early on. and then the patients do have reparative capacity. we know that. and we try to do studies to promote that.”
he also highlights findings around a different cell type in ms “that just kind of smoulders away in the brain” that’s brought a panel of new drugs called btk inhibitors that potentially slow progression in both relapsing and progressive forms of ms. the beauty of this drug is that it is small enough to get across the blood-brain barrier into the brain, where larger molecules are blocked to protect the brain from harm.
new drugs hold promise for halting ms
“we know if [the btk inhibitor] encounters some of those cells that we think are responsible for that smouldering inflammation, that the interaction, at least from what we’ve seen in animals and in vitro studies, turns those cells off. maybe that will turn off the progression.”
he points to the hercules phase 3 study that looked at the btk tolebrutinib, resulting in a reduction in disability accumulation in non-relapsing secondary-progressive ms.
“the non-relapsing meant that they no longer had that inflammation that we can target, even with a bone marrow transplant. they are just slowly progressing in a non-inflammatory way. and if you gave those patients tolebrutinib, it slowed that progression. i think we can mitigate against any of those risks and hopefully get that drug in canada so we can offer that group of patients something. and we’re going to learn from treating them, of course, because there are going to be those that are resistant and those that are not, but we’ll learn from doing that.”
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