Progressive multiple sclerosis (PMS) has long posed a challenge due to its lack of effective treatments that target both the immune system and nerve health. In contrast to relapsing-remitting MS (RRMS), PMS is marked by a steady progression of disability, for which neuroprotection and immunomodulation are critical. Recent studies in animals have shown promise with neural precursor cell (NPC) transplants, which appear to protect and repair nervous tissue.
The primary objective of Genchi et al.’s STEMS study was to assess if hfNPC transplantation is feasible and safe for patients with PMS. hfNPCs, derived from human fetal cells, can potentially repair damaged nervous tissue by releasing molecules that support nerve growth and reduce inflammation.
Safety and Tolerability of hfNPC
The study’s main focus was safety, particularly looking for severe adverse reactions linked to hfNPCs. At the two-year mark, no serious adverse events were attributed to the treatment, supporting the idea that hfNPC therapy is safe and well-tolerated for this patient group. Although mild or moderate side effects occurred in some patients, no cases were related directly to the hfNPCs. While one patient experienced a relapse of their MS symptoms, the authors point out that this was likely due to prior treatments rather than the experimental cell therapy.
Some patients developed new MRI-visible brain lesions, although these were not linked to clinical relapses and appeared to be part of the typical progression of PMS.
While mild side effects occurred, hfNPC treatment did not produce any severe or unexpected safety concerns in this preliminary trial.
Potential Benefits of hfNPC Treatment
In addition to the safety findings, this study provided early signs that hfNPCs might benefit brain health in PMS. Patients receiving the highest dose of hfNPCs showed lower rates of brain atrophy, or brain tissue loss, compared to typical progression rates. Brain atrophy is common in advanced MS and closely associated with increasing disability.
Importantly, Genchi et al. also found an increase in certain protective molecules in patients’ spinal fluids, which may help reduce inflammation and support nerve repair. These results hint that hfNPCs could potentially protect brain cells and foster nerve regeneration, although more research is needed to confirm these effects.
Brain Changes and hfNPC Impact
Reducing brain atrophy in MS is complex because brain volume can change for many reasons, including fluid shifts linked to inflammation. Despite these complexities, the authors found that the correlation between reduced brain atrophy and the number of hfNPCs injected remained robust even after adjusting for age, baseline disability, and other factors. These observations, while preliminary, suggest that hfNPCs may play a role in slowing brain degeneration in PMS patients.
Changes in Protective and Immune Molecules
The study also found notable changes in certain protective and immune molecules in patients’ cerebrospinal fluid (CSF) three months after treatment. Some molecules, such as GDNF and VEGF-C, are known to support neuron growth and nerve cell survival, while others, such as IL-10, have anti-inflammatory properties. Although patients were also receiving other treatments that may have influenced these results, Genchi et al. believe the rise in these molecules could imply that hfNPCs helped foster a neuroprotective environment.
Interestingly, while certain inflammatory markers also increased, they may support nerve regeneration under specific conditions. For instance, IL-15, an immune molecule, also regulates nerve cell development and may contribute to nerve repair. However, the study cannot definitively confirm that hfNPCs alone caused these changes, and the authors call for further trials to analyze this effect in more detail.
Cognitive and Functional Changes
One notable result was that patients showed improvement in cognitive scores, specifically in tests measuring processing speed. While the improvement may partially be due to practice effects (familiarity with the tests), it suggests that hfNPCs might help maintain cognitive function in PMS patients. Patients with the most significant cognitive difficulties before treatment showed the most improvement, though more studies are needed to understand the impact of hfNPCs on cognition fully.
Study Limitations and Future Directions
Since this early-phase trial was designed to test safety rather than efficacy, the author’s conclusions about potential benefits are limited. The small sample size and lack of a placebo control group mean that results should be interpreted cautiously. Additionally, MRI lesion activity increased in some patients, raising questions about how hfNPCs interact with the disease over time. Larger, controlled trials are needed to validate these findings and determine if hfNPCs can meaningfully slow or reverse brain damage and disability in PMS.
The researchers also noted that hfNPCs might provide lasting benefits by continuing to release protective molecules months after the initial transplant. However, the study’s short follow-up period does not allow for a complete understanding of how long these cells remain active in the body.
The Future of hfNPC Therapy in PMS
Genchi et al.’s STEMS trial provides early evidence that hfNPC therapy is feasible, safe, and potentially beneficial for patients with PMS. Although preliminary, the findings suggest that hfNPCs may help reduce brain tissue loss and support nerve repair by increasing levels of protective and anti-inflammatory molecules in the spinal fluid. These early outcomes pave the way for larger studies that will more rigorously evaluate whether hfNPCs can slow PMS progression and improve patient outcomes.
For now, hfNPC therapy shows promise as an innovative approach that could address the unmet needs of patients with PMS, particularly by combining neuroprotection and immune modulation to combat progressive disability. As this research progresses, it may represent a meaningful step forward in treating this challenging form of multiple sclerosis.
Source: Genchi, A., Brambilla, E., Sangalli, F. et al. Neural stem cell transplantation in patients with progressive multiple sclerosis: an open-label, phase 1 study. Nat Med 29, 75–85 (2023). https://doi.org/10.1038/s41591-022-02097-3
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