Multiple sclerosis (MS) is a chronic disease that affects the central nervous system, disrupting the way the brain and spinal cord communicate with the rest of the body. Over the years, researchers have developed many treatments that have transformed the outlook for patients with relapsing-remitting MS (RRMS), the most common form of the disease. Unfortunately, these advances have not been as effective for people with progressive MS (PMS), a form of the condition where symptoms steadily worsen over time without clear periods of recovery.
For patients with PMS, there is still an urgent need for new therapies that do more than slow the disease. Treatments must protect the brain and spinal cord, calm harmful immune responses, and even help repair damage that has already been done. Researchers are exploring innovative ways to meet this challenge, and one of the most exciting possibilities lies in the use of neural stem cells.
In this review, Genchi et al. present the results of STEMS, a prospective, therapeutic exploratory, non-randomized, open-label, single-dose-finding phase 1 clinical trial.
Understanding Neural Stem Cells
Neural stem cells are special cells found in the brain and spinal cord. They can divide and create new cells, and they have the unique ability to develop into different types of brain cells, including neurons, astrocytes, and oligodendrocytes. These cells not only replace damaged tissue but also support the surrounding environment, release helpful molecules, and guide repair processes.
Early research once assumed that stem cell therapy worked only by replacing lost cells. Now, scientists know the story is much more complex. Neural stem cells can remain in an immature state and still have powerful effects. They can interact with the body’s own cells, regulate immune activity, and send out signals that protect nerves from further harm. This “bystander effect” is now seen as one of the most important ways stem cells may help patients with PMS.
The STEMS Clinical Trial
The STEMS trial was the first phase 1 study to test the safety of transplanting human fetal neural precursor cells (hfNPCs) into patients with progressive MS. The cells were delivered directly into the fluid surrounding the spinal cord, a method known as intrathecal injection.
The main goal was safety—primarily, if the treatment could be given without causing serious harm. At the same time, the authors explored whether the cells might show early signs of benefit, such as protecting brain volume or improving certain cognitive functions.
Safety Outcomes of the Trial
The results of this study were encouraging. Over a two-year follow-up period, the authors found no severe side effects directly linked to the transplanted cells were observed. Most side effects were mild or moderate, such as headaches or temporary discomfort.
One patient experienced a relapse of MS symptoms, but this was not thought to be caused by the stem cell therapy. Some patients developed new spots of inflammation on MRI scans, but these were considered part of the natural disease process rather than a direct result of the treatment. Importantly, no evidence suggested that the therapy caused dangerous or uncontrolled growth of cells in the nervous system.
Potential Benefits of Neural Stem Cell Therapy
Although the trial was small and not designed to prove effectiveness, Genchi et al. noticed several promising trends.
Slowing Brain Volume Loss
Brain shrinkage, also known as atrophy, is a hallmark of progressive MS and is strongly linked to worsening disability. In the trial, patients who received higher doses of stem cells showed a slower rate of brain and gray matter shrinkage over two years. This suggests the therapy may have a protective effect on the nervous system.
Cognitive Improvements
Another surprising finding was improvement in a test of processing speed, a measure of how quickly someone can understand and respond to information. While practice effects may have played a role, the fact that patients with worse baseline scores improved the most hints at a real therapeutic effect.
Biological Signals of Repair
Spinal fluid samples taken from patients showed higher levels of certain molecules linked to nerve protection, immune regulation, and tissue repair. For example, increases in growth factors such as GDNF and VEGF-C suggested that the transplanted cells were encouraging the nervous system to heal itself. Other changes hinted at reduced inflammation, which is critical in slowing progression of MS.
The Complex Picture of Inflammation
Not all findings were straightforward. Some patients developed new inflammatory spots on brain scans, even though they did not experience relapses. The authors could not find a clear link between the number of transplanted cells and the amount of new inflammation, but they caution that more work is needed to understand this pattern.
Interestingly, some molecules that are usually considered pro-inflammatory also play roles in nerve repair and stem cell activity. For instance, increases in IL-15 and GM-CSF could be seen as either harmful or helpful depending on context. This highlights how complex the immune system is in MS and why therapies must be carefully studied in larger groups of patients.
Limitations of the Study
While the findings are promising, it is important to keep in mind the limitations. The trial included only a small number of patients and did not have a control group for comparison. The follow-up period of two years may not be long enough to understand the full effects of stem cell therapy, especially since progressive MS changes slowly.
Measures of disability, such as the Expanded Disability Status Scale (EDSS), showed little change. However, this scale is not very sensitive in patients who already have significant disability, and the inclusion criteria may have created bias. Tests of hand function suggested mild worsening, though this was expected given the disease stage.
Significance for Progressive MS
Despite these challenges, the STEMS trial marks an important step forward. For the first time, the authors demonstrated neural stem cells to be safe and well-tolerated when transplanted into patients with PMS. Early signals suggest they may protect the brain, slow shrinkage, and create a more supportive environment for repair.
Progressive MS is notoriously difficult to treat because it involves ongoing nerve loss and scarring, not just inflammation. By targeting multiple processes at once—immunomodulation, neuroprotection, and regeneration—stem cells may offer something no current therapy can.
Looking Ahead: Next Steps in Research
According to the authors, the next step is larger clinical trials that test the therapy in more patients and include control groups for comparison. Researchers will also need to refine dosing, understand how long the transplanted cells survive, and determine whether benefits can be sustained over many years.
Future studies may explore combining stem cell therapy with existing MS treatments to maximize effectiveness. Scientists also hope to learn whether neural stem cells can not only protect the brain but also restore lost function, offering real improvements in quality of life.
A Cautious but Hopeful Outlook
For now, patients with progressive MS should view neural stem cell therapy as an experimental but hopeful avenue. While it is too early to say whether it will become a standard treatment, the early signs suggest that it has the potential to slow progression and improve aspects of brain health.
The STEMS trial demonstrates the importance of moving beyond symptom management and exploring treatments that directly target the mechanisms of neurodegeneration. Neural stem cells could represent a powerful new tool in the fight against progressive MS, but much more research is needed.
Source: Genchi A, Brambilla E, Sangalli F, Radaelli M, Bacigaluppi M, Furlan R, Andolfo A, Drago D, Magagnotti C, Scotti GM, Greco R, Vezzulli P, Ottoboni L, Bonopane M, Capilupo D, Ruffini F, Belotti D, Cabiati B, Cesana S, Matera G, Leocani L, Martinelli V, Moiola L, Vago L, Panina-Bordignon P, Falini A, Ciceri F, Uglietti A, Sormani MP, Comi G, Battaglia MA, Rocca MA, Storelli L, Pagani E, Gaipa G, Martino G. Neural stem cell transplantation in patients with progressive multiple sclerosis: an open-label, phase 1 study. Nat Med. 2023 Jan;29(1):75-85. doi: 10.1038/s41591-022-02097-3. Epub 2023 Jan 9. PMID: 36624312; PMCID: PMC9873560.
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