Image credit: Signals
Cells that are programmed to protect can sometimes go rogue, as is the case with multiple sclerosis, or MS. Overactive immune cells mistakenly target the tissues of the brain, spinal cord and optic nerves, igniting inflammatory flare-ups that destroy myelin, a fatty insulating material that encapsulates nerve fibres. Over time, nerves lose their ability to transmit signals, and mobility, cognitive functions and vision take a serious hit.
There is no known cure for MS but researchers believe that by harnessing the natural healing properties of stem cells, they may offer hope to the 2.8 million MS patients worldwide. Canadian researchers have led global research efforts to investigate whether mesenchymal stem cells (MSCs) can slow symptom progression and perhaps even repair central nervous system damage and restore function.
A recently published report featured in The Lancet Neurology describes outcomes from MEsenchymal StEm cells for Multiple Sclerosis (MESEMS)—an international, multi-site clinical trial led by neurology expert Prof. Mark Freedman from The Ottawa Hospital Research Institute.
MESEMS yielded a mixed bag of results. There were triumphs, disappointments and new questions to spur future studies. I caught up with Dr. Freedman to take a deep dive into the study’s results and what this means for the future of cell therapies for MS.
Dr. Freedman has dedicated over 25 years to helping MS patients and he is recognized for his exceptional contributions to stem cell research alongside fellow stem cell pioneer, Dr. Harold Atkins. His interest in MS was sparked during his neurology residency when he received the devastating news that a former colleague had been diagnosed with the autoimmune disease. A heart-to-heart conversation with his friend set him on his current path.
“He planted the seed, and I never looked back,” said Dr. Freedman.
From the early years, Dr. Freedman and colleagues were interested in finding ways of rebooting the immune system in patients with aggressive MS. This immune kickstart is an exceedingly ambitious goal. MS is a disease that unfolds and worsens gradually over decades, involving a complex mix of circulating immune cells and those that reside within tissues of the central nervous system.
Also, pinpointing the genetic controllers of the disease is tricky; there are over 100 gene variants that influence predisposition to the disease. Plus, environmental factors also factor in, making every MS case unique.
The first clue that MSCs might help was when Dr. Freedman showed that bone marrow stem cells could slow down progressive nerve damage. This and other studies reporting similar results made it clear that MSCs deserved a closer look.
The process of harvesting and cultivating MSCs from patients’ bone marrow was already an established technique at the time. Therefore, it could be truly transformational (and relatively easy to translate to a clinical setting) if researchers could demonstrate that MSCs could alleviate MS symptoms and improve patients’ quality of life.
A decade ago, MS researchers began mobilizing to investigate the full potential of MSCs’ regenerative capabilities. “We wondered whether MSCs might be capable of repairing previous damage,” explained Dr. Freedman. Several experts consolidated their findings and recommendations that MSCs be considered as a treatment modality for MS patients, publishing these as a consensus in the Multiple Sclerosis Journal.
Flash forward to the 2021 MESEMS trial—did MSCs live up to their expectations?
First, let’s look at the trial framework:
- 144 participants with active MS who haven’t responded to existing therapies;
- The cohort was spread across 15 sites in nine countries;
- Participants received a single dose of marrow-derived MSCs (or a placebo), given intravenously; and,
- After six months, researchers assessed patients for signs of reduced inflammation and repair of central nervous system tissues.
On the plus side, the MSCs were safe and well-tolerated by the trial participants. In addition, there was a trend where those who got the treatment were less likely to relapse, but these numbers were not statistically significant.
Disappointingly, however, the data did not support the hypothesis that MSCs could heal and repair MS lesions. Dr. Freedman doesn’t see these results as a setback, but instead believes they open a myriad of new avenues to explore.
“Just because we could not show that ability with the protocol as we outlined, it does not rule out that they may nevertheless be capable of doing so, under the right conditions,” he said.
How patients receive MSCs appears to matter. When physicians inject the cells into the bloodstream, they collect in the lungs en route to the sites of neural injury. Here’s where cell therapy experts are divided: Dr. Freedman says some see the lungs as an immunological organ where MSCs get programmed to exert their healing effects.
“Others feel that the cells do not need whatever processing the lung might have and want to inject them directly intrathecally,” he said.
This is just one of many nuances in the cell therapy protocol that Dr. Freedman says has the potential to be optimized. For example, some techniques call for cells to be extracted from the patients, and frozen until they are ready to be thawed and administered. Others believe that briefly culturing MSCs after thawing may ignite their healing properties, making them more clinically beneficial. The dose and frequency of treatments also play a role in impacting patient outcomes.
We know that MSCs are potent anti-inflammatories. They release soluble factors that help resist graft rejection in bone marrow transplant patients, alleviate colitis symptoms, manage ischemic heart disease, and may even calm the cytokine storms associated with severe COVID cases. However, we don’t know whether MSCs work equally well across all types of inflammation and whether MS lesions fall within a group that can benefit from MSCs.
According to Dr. Freedman, reducing inflammation wasn’t their prime target. “We did not really even care if we could reduce enhancing lesions on MRI since we have plenty of drugs that can do that now,” he said.
“We were hoping to use inflammation as a biological signal of repair – the real hope of these cells.”
Their next mission is to attempt to reduce the heterogeneity between MSC culture protocols, unifying the methodologies employed in different countries and facilities. A single source of cells cultured in a single facility may help to lessen the variability of patient outcomes, as noted in MESEMS.
The team is proud of the research wins accumulated over decades of hard work, which are the light at the end of the tunnel for MS patients. “The fact that we showed the ability to obtain MSCs, grow them successfully in a laboratory, and put them back safely into patients in numerous different countries is no small feat,” remarked Dr. Freedman.
He added that safety is one of the major obstacles facing therapies on the path to commercialization. With no significant adverse events noted among MESEMS participants, Dr. Freedman’s team continues their work towards unlocking the full potential of MSCs for healing MS patients.
Tara Fernandez
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