The bumpy road to treating multiple sclerosis with stem cells

For some people, the attacks start as sudden and recurring. For others, it is a slow, smoldering progression. Despite advancements in our understanding of the causes of multiple sclerosis (MS), a narrow selection of treatment options are available for the wide range of patient experiences. 

Aggressive treatment with immune-modifying drugs early in the disease course can mitigate the wear and tear of MS by reducing relapse and slowing down the body’s attack on brain cells. However, there is no cure for MS, and very few treatment options exist for patients with advanced forms of the disease. Stem cell therapies for MS first emerged as promising candidates nearly two decades ago, but their success in the clinic has been limited, and public misunderstanding of these therapies threatens their legitimacy.

Putting the brakes on inflammation

“Stem cell” is a catchall term for any cell that can differentiate into another cell type. Hematopoietic stem cells (HSC) originate from bone marrow to replenish blood cells. Researchers originally developed a procedure called HSC transplantation (HSCT), which involves harvesting HSCs from a patient’s bone marrow followed by intense immune cell depletion and HSC reintroduction, to treat blood cancers. Now, scientists are investigating HSCT for treating MS. 

In MS, the immune system mistakenly attacks nerve cells in the brain. Researchers think that a failure in the braking system of proinflammatory pathways leads to brain inflammation. The rationale behind HSCT for MS is that it provides a tune-up by wiping out the faulty immune system and starting anew. Indeed, there is evidence that following the elimination of adaptive and innate immune cells, HSCs progressively rebuild the immune system (1). The removal of the destructive immune cells paves the way for a new and improved immune repertoire, including naïve T cells, which help suppress inflammatory disease activity. Evidence suggests that HSCT is most effective for the niche of patients early in their disease course when the immune system is most active, such as in the case of relapsing-remitting MS (RRMS) (2). 

HSCT, however, does have some downsides. Most studies of HSCTs are observational cohort studies, and the dearth of clinical studies that directly compare HSCT with other approved therapies hinders understanding of the benefits of the procedure. Crucially, the intense immune suppression inherent to the procedure is associated with a three to five percent mortality rate (2). 

While this may be acceptable in the face of deadly cancers, it is a big risk for people with a disease like MS. Thus, clinicians currently only offer HSCT to individuals with active MS where available treatments have failed. Several ongoing clinical studies, including the RAM-MS, BEAT-MS, and StarMS trials, hope to shine a light on how HSCT stacks up against available therapies.

A trip to the repair shop

Over time, the immune system’s sustained attack damages nerve cells’ protective myelin shells and produces lesions. Myelin is a fatty layer of insulation covering cells and is responsible for rapid communication between nerve cells. Progressive MS develops over time as a result of a failure to repair myelin. While HSCT effectively resolves inflammation, there is little proof that it slows disease progression or provides benefits to patients with more advanced forms of MS. 

Mesenchymal stromal cells (MSCs) are stem cells that are abundant in the bone marrow and connective tissues of organs. In addition to their immunosuppressive properties, these diverse cells are multipotent and self-replicating, making them attractive candidates for tissue repair. Researchers hope that MSCs will rein in unchecked immune activity and stimulate repair in one fell swoop. 

I would be very cautious because this is a phase 1 study, and making strong claims is dangerous for the field, for the community, for the patient, and especially for phase 2 trials because they might create a misperception. 
– Stefano Pluchino, University of Cambridge

The preclinical evidence is promising. MSCs secrete factors that promote cell growth and survival (3,4), suppress T cell proliferation (5), and inhibit the production of proinflammatory cytokines (6). “They also are very migratory cells, so they tend to seek out inflammation or areas of damage,” said Jeffrey Cohen, a neurologist specializing in MS at the Cleveland Clinic. 

Although MSCs are generally safe and well tolerated in patients with MS, “efficacy data out of phase 2 clinical trials is very, very limited,” said Stefano Pluchino, a neuroimmunologist at the University of Cambridge. 

A large number of small clinical studies (many of which are uncontrolled) have produced mixed results (7). In one high-profile, placebo-controlled trial, the MESEMS study, researchers provided support for the safety of a single intravenous dose of bone marrow-derived MSCs in people with MS, but failed to find any evidence of reduced lesion activity (8). In contrast, another study revealed that MSCs reduced signs of disease activity, including fewer lesions and improved motor and cognitive functioning, in patients with active disease (9). MSCs infused directly into cerebrospinal fluid produced a greater response on these measures of disease activity than intravenous administration (9). 

Cohen and his colleagues recently published that customizing MSCs may augment their repair capabilities. In a small, uncontrolled, phase 2 trial of patients with progressive MS, researchers modified MSCs in the lab to secrete an array of neurotrophic factors before reintroducing them into the cerebrospinal fluid (10). Neurotrophic factors are molecules that promote cell growth and survival, and scientists hypothesize that MSCs optimized to release neurotrophic factors will promote the repair of damaged nerve cells. Relative to baseline measures of cerebrospinal fluid, the researchers observed increased neuroprotective factors and decreased inflammatory biomarkers following treatment with the modified MSCs. In this study, scientists introduced MSCs in the culture dish to a mixed bag of neurotrophic factors. The team’s long-term goal is to link specific neurotrophic factors to better patient outcomes.

Getting closer to home

Damage to the protective myelin sheath surrounding nerve cells and a loss of connectivity between brain cells dominate late, inactive phases of MS. MSCs are unlikely to address these problems given their limited ability to mature into brain cells in vivo (11). For this, a more specialized mechanic is needed. 

Neural stem cells (NSCs) are self-renewing and differentiate into neural and glial cells in the brain. “Across preclinical models of MS, we have observed remarkable evidence of NSCs’ therapeutic effect, spanning from what was expected to what was not expected at all,” said Pluchino. 

These results include evidence of remyelination, decreased glial scar formation, and reduction of macrophage and microglial activation in the brain (7, 11). “These are findings that are consistent over the years, over independent laboratories, and over the different models of MS,” said Pluchino.

The ability of NSCs to travel to damaged areas and promote structural and functional repair makes them great candidates for treating progressive MS. However, ethical concerns surrounding one source of NSCs — embryonic stem cells — have hindered their clinical study in MS. Inducible NSCs (iNSCs), which are directly induced from a patient’s tissue, and induced pluripotent stem cells (iPSCs) are alternatives sources of NSCs currently under investigation. 

There's a lot of work going on in this area, so hopefully we will start to see some tangible progress. 
– Jeffrey Cohen, Cleveland Clinic

A recent phase 1 trial published in Nature Medicine highlighted the feasibility and safety of transplanting neural stem cells into the spinal fluid of people with progressive MS (12). Additional analyses suggest that NSCs increase levels of anti-inflammatory and neuroprotective factors in the cerebrospinal fluid. Although promising, “I would be very cautious because this is a phase 1 study, and making strong claims is dangerous for the field, for the community, for the patient, and especially for phase 2 trials because they might create a misperception,” said Pluchino. Despite the strong preclinical evidence for NSCs, there is still little clinical data to support their use in MS.

It is still early days for stem cell therapy for MS. Overall, researchers face several technical challenges and practical complications when implementing cell-based therapy. The success of a particular stem cell therapy is subject to the dosing, route of administration, source of the stem cell, and timing of administration. On top of this, a track record of small, uncontrolled clinical trials hinders the evaluation of the benefits of stem cell therapy over currently available treatments for MS. 

“There's a lot of work going on in this area, so hopefully we will start to see some tangible progress,” said Cohen. 

References

1. Muraro, P.A. et al. Thymic output generates a new and diverse TCR repertoire after autologous stem cell transplantation in multiple sclerosis patients. J Exp Med  201, 805-816 (2005).
2. Muraro, P.A. et al. Autologous haematopoietic stem cell transplantation for treatment of multiple sclerosis. Nat Rev Neurol  13, 391-405 (2017).
3. Cho, J.S. et al. Transplantation of mesenchymal stem cells enhances axonal outgrowth and cell survival in an organotypic spinal cord slice culture. Neurosci Lett  454, 43-48 (2009).
4. Kim, H.J. et al. Therapeutic effects of human mesenchymal stem cells on traumatic brain injury in rats: secretion of neurotrophic factors and inhibition of apoptosis. J Neurotrauma  27, 131-138 (2010).
5. Glennie, S. et al. Bone marrow mesenchymal stem cells induce division arrest anergy of activated T cells. Blood  105, 2821-2827 (2005).
6. Puissant, B. et al. Immunomodulatory effect of human adipose tissue-derived adult stem cells: comparison with bone marrow mesenchymal stem cells. Br J Haematol  129, 118-129 (2005).
7. Smith, J.A. et al. Stem cell therapies for progressive multiple sclerosis. Front Cell Dev Biol  9, 696434 (2021).
8. Uccelli, A. et al. Safety, tolerability, and activity of mesenchymal stem cells versus placebo in multiple sclerosis (MESEMS): A phase 2, randomised, double-blind crossover trial. Lancet Neurol  20, 917-929 (2021).
9. Petrou, P. et al. Beneficial effects of autologous mesenchymal stem cell transplantation in active progressive multiple sclerosis. Brain  143, 3574-3588 (2020).
10. Cohen, J.A. et al. Evaluation of neurotrophic factor secreting mesenchymal stem cells in progressive multiple sclerosis. Mult Scler  29, 92-106 (2023).
11. Pluchino, S. et al. Promises and limitations of neural stem cell therapies for progressive multiple sclerosis. Trends Mol Med  26, 898-912 (2020).
12. Genchi, A. et al. Neural stem cell transplantation in patients with progressive multiple sclerosis: an open-label, phase 1 study. Nat Med  29, 75-85 (2023).
13. Bauer, G. et al. Concise review: A comprehensive analysis of reported adverse events in patients receiving unproven stem cell-based interventions. Stem Cells Transl Med  7, 676-685 (2018).