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Breakthrough stem cell therapy shows significant promise in halting Multiple Sclerosis

[Nov. 28, 2023: JJ Shavit, The Brighter Side of News]

Duchenne muscular dystrophy (DMD) is a severe genetic disorder that leads to progressive muscle weakness. (CREDIT: Creative Commons)

In a groundbreaking development, an international team of researchers has conducted a pioneering clinical trial, demonstrating the safety and potential efficacy of injecting neural stem cells into the brains of patients with progressive multiple sclerosis (MS).

Led by scientists from the University of Cambridge, the University of Milan Bicocca, and Hospital Casa Sollievo della Sofferenza in Italy, this study represents a significant stride toward advancing cell therapy for the treatment of progressive MS, a debilitating disease affecting over 2 million people worldwide.


Multiple sclerosis is a chronic autoimmune disease characterized by the immune system's misguided attack on myelin, the protective sheath enveloping nerve fibers. This relentless assault disrupts the transmission of vital neural signals within the brain and spinal cord, leading to a range of debilitating symptoms.

Although treatments are available to mitigate the severity and frequency of relapses, a disheartening two-thirds of MS patients eventually transition to a secondary progressive phase of the disease, characterized by an inexorable deterioration of their condition.


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The Role of Microglial Cells

Central to the pathophysiology of progressive MS are microglial cells, a subtype of macrophages responsible for patrolling the central nervous system (CNS). In progressive forms of MS, these microglial cells become rogue agents, causing chronic inflammation and nerve cell damage.

Recent scientific advancements have spurred optimism that stem cell therapies might hold the key to mitigating this destructive process. Stem cells, often referred to as the body's "master cells," can be reprogrammed to develop into various cell types, making them a promising avenue for treating MS.


Prior work by the Cambridge team had shown in mice that stem cells derived from reprogrammed skin cells, when transplanted into the CNS, could reduce inflammation and potentially contribute to repairing MS-induced damage. Building on this foundation, the researchers embarked on a first-in-human clinical trial, the results of which have now been published in the journal Cell Stem Cell.

Graphical Abstract: An advanced therapy with neural stem/progenitor cells (NSCs) is feasible in humans. (CREDIT: Cell Stem Cell)

The clinical trial involved the direct injection of neural stem cells into the brains of 15 patients with secondary progressive MS, recruited from two Italian hospitals. This international collaboration also included researchers from the University of Colorado (USA) and the Ente Ospedaliero Cantonale in Lugano, Switzerland. The stem cells used in the trial were sourced from a single fetal donor's brain tissue, a breakthrough that could eventually lead to a virtually limitless supply of these cells. Future developments may even enable the derivation of these cells directly from the patient, addressing practical challenges associated with the use of allogeneic fetal tissue.


A Year of Observations: Safety and Stability

Over a 12-month period, the research team diligently monitored the patients, and the results were nothing short of promising. Notably, there were no treatment-related deaths or serious adverse events observed during the study. Although some participants experienced temporary or reversible side effects, none of these issues raised significant concerns.

Non-clinical parameters of the hNSC 03/14b line after ISI or ICVI in the CNS of healthy immunodeficient mice. (CREDIT: Cell Stem Cell)

At the outset of the trial, all patients exhibited high levels of disability, with many requiring wheelchairs. However, over the 12-month follow-up period, there was no indication of increased disability or a worsening of symptoms. Remarkably, none of the patients reported symptoms indicative of an MS relapse, and cognitive function remained stable. While it is challenging to confirm complete disease stability due to the initial high levels of disability, these findings suggest substantial disease stability.


The Role of Stem Cell Dosage

The research team also investigated the relationship between stem cell dosage and brain tissue volume associated with disease progression. Their findings indicated that the higher the dose of injected stem cells, the smaller the reduction in brain volume over time. This intriguing observation hints at the possibility that stem cell transplantation may help dampen inflammation within the CNS.

(A) Thin-slice cranial CT or MRI scans allow the evaluation of the ventricular system. (B–F) Frameless stereotactic image guidance AxiEM system used to perform the ventricular cannulation. Correct catheter placement is verified based on the egress of CSF, and a Rickham reservoir is then connected to it. (CREDIT: Cell Stem Cell)

Beyond assessing disease stability, the researchers delved into whether the injected stem cells had a neuroprotective effect, shielding nerve cells from further damage. Previous research had highlighted the role of metabolic changes in reprogramming microglia from "bad" to "good." In this study, the team examined alterations in brain metabolism post-treatment. By measuring changes in the fluid surrounding the brain and in the bloodstream, they identified signs related to how the brain processes fatty acids. These signs were not only associated with the effectiveness of the treatment but also correlated with disease progression. Intriguingly, the study revealed that higher stem cell dosages were linked to increased levels of fatty acids, a trend that persisted over the 12-month observation period.


Professor Stefano Pluchino, co-lead investigator from the University of Cambridge, expressed cautious optimism about the findings, stating, "We desperately need to develop new treatments for secondary progressive MS, and I am cautiously very excited about our findings, which are a step towards developing a cell therapy for treating MS. 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."

Longitudinal metabolomics and lipidomics analyses of CSF and serum. (A) Experimental design. (B and C) Linear discriminant analyses (LDAs) identify an effect of ACT hNSC 03/14b line dose and time (z axis) on the metabolic phenotypes with a clear dose-dependent gradient in the CSF (B), but not in the serum (C). (CREDIT: Cell Stem Cell)

Co-lead investigator Professor Angelo Vescovi from the University of Milano-Bicocca added, "It has taken nearly three decades to translate the discovery of brain stem cells into this experimental therapeutic treatment. This study will add to the increasing excitement in this field and pave the way to broader efficacy studies, soon to come."


The Perspective of the MS Society

Caitlin Astbury, Research Communications Manager at the MS Society, offered her perspective on the study, saying, "This is a really exciting study which builds on previous research funded by us. These results show that special stem cells injected into the brain were safe and well-tolerated by people with secondary progressive MS. They also suggest this treatment approach might even stabilize disability progression.

Normalized volume of T2 lesions between the run-in-END and month 12 according to the four different doses of ACT hNSC 03/14b: 5, 10, 16, and 24 million cells. Each line is an individual patient. (CREDIT: Cell Stem Cell)

We've known for some time that this method has the potential to help protect the brain from progression in MS. This was a very small, early-stage study, and we need further clinical trials to find out if this treatment has a beneficial effect on the condition. But this is an encouraging step towards a new way of treating some people with MS."


While further research and larger clinical trials are needed to confirm the findings and expand our understanding of this promising therapy, the study represents a significant milestone on the path toward a new way of treating MS and improving the lives of millions of individuals worldwide.

For more science news stories check out our New Innovations section at The Brighter Side of News.


Note: Materials provided above by UBC Faculty of Medicine. Content may be edited for style and length.


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