University of Colorado Anschutz Medical Campus researchers are part of an international team that has shown that the injection of a type of stem cell into the brains of patients living with progressive multiple sclerosis (MS) is safe, well tolerated and has a long-lasting effect that appears to protect the brain from further damage.
The study was published in Cell Stem Cell.
The collaborative study by researchers at CU Anschutz, the University of Cambridge and the University of Milano-Bicocca is a step toward developing an advanced cell therapy treatment for progressive MS, for which no treatments currently exist.
Over 2 million people live with MS, and while treatments exist that can reduce the severity and frequency of relapses, two-thirds of MS patients still transition into a debilitating secondary progressive phase of disease within 25-30 years of diagnosis, where disability grows steadily worse.
In MS, the body’s own immune system attacks and damages myelin, the protective sheath around nerve fibres, causing disruption to messages sent around the brain and spinal cord.
Programming ‘master cells’
Key immune cells involved in this process are macrophages (literally “big eaters”), which ordinarily attack and rid the body of unwanted intruders. A particular type of macrophage known as a microglial cell is found throughout the brain and spinal cord. In progressive forms of MS, they attack the central nervous system (CNS), causing chronic inflammation and damage to nerve cells.
Recent advances have raised expectations that stem cell therapies might help ameliorate this damage. These involve the transplantation of stem cells, the body’s “master cells,” which can be programmed to develop into almost any type of cell within the body.
Previous work from the Cambridge team has shown in mice that skin cells reprogrammed into brain stem cells, transplanted into the central nervous system, can help reduce inflammation and may be able to help repair damage caused by MS.
Together, the international team has completed a first-in-human, early-stage clinical trial that involved injecting neural stem cells directly into the brains of 15 patients with secondary MS recruited from two hospitals in Italy.
The stem cells were derived from cells taken from brain tissue from a single, miscarried fetal donor. From this single donor, the team says it would be possible to produce a virtually limitless supply of these stem cells – and in the future it may be possible to derive these cells directly from the patient – helping overcome potential ethical and practical problems associated with the use of fetal tissue.
Substantial stability of the disease
The team followed the patients over 12 months, during which time they observed no treatment-related deaths or serious adverse events. While some side-effects were observed, all were either temporary or reversible.
All the patients showed high levels of disability at the start of the trial – most required a wheelchair, for example – but during the 12-month follow-up period none showed any increase in disability or a worsening of symptoms. None of the patients reported symptoms that suggested a relapse and nor did their cognitive function worsen significantly during the study. Overall, the researchers say, this points to a substantial stability of the disease, without signs of progression, though the high levels of disability at the start of the trial make this difficult to confirm.
The researchers assessed a subgroup of patients for changes in the volume of brain tissue associated with disease progression. They found that the larger the dose of injected stem cells, the smaller the reduction in brain volume over time. They speculate that this may be because the stem cell transplant dampened inflammation.
The team also looked for signs that the stem cells were having a neuroprotective effect –protecting nerve cells from further damage. Their previous work showed how tweaking metabolism – how the body produces energy – can in turn reprogram microglia from “bad” to “good.”
‘Safe but also promising’
The lab of Angelo D’Alessandro, PhD, a professor at the CU School of Medicine, had already been working with Cambridge in basic science investigations aimed at understanding the metabolic underpinnings of neurodegeneration in multiple sclerosis, with a special focus on the role of metabolic signals driving inflammatory events that make immune cells in the brain turn against neurons.
“When samples from this breakthrough trial became available, CU was offered the unique opportunity to directly investigate the molecular impact of transplantation of neural stem cells in the brains of multiple sclerosis patients,” D’Alessandro said. “This breakthrough approach turned out not only to be safe but also promising, with respect to the effects observed through medical exams and, as data generated in our lab suggest, molecular markers of neuroinflammation."
D’Alessandro and the teams looked at how the brain's metabolism changes after the treatment. The researchers measured changes in the fluid around the brain and in the blood over time and found certain signs that are linked to how the brain processes fatty acids. These signs were connected to how well the treatment works and how the disease develops. What’s more, the higher the dose of stem cells, the greater the levels of fatty acids, which also persisted over the 12-month period.
“We desperately need to develop new treatments for secondary progressive MS, and I am cautiously very excited about our findings, which are a step toward developing a cell therapy for treating MS,” Professor Stefano Pluchino from the University of Cambridge, who co-led the study, said.
“We recognize that our study has limitations – it was only a small study and there may have been confounding effects from the immunosuppressant drugs, for example – but the fact that our treatment was safe and that its effects lasted over the 12 months of the trial means that we can proceed to the next stage of clinical trials,” Pluchino added.
February 20, 2024