Stem cells for MS: progress and perspective

Here’s another one that ‘got away’ – an article on various stem cell therapy-based approaches for multiple sclerosis that I wrote this past August, originally slated for a special collection that fell through at more or less the last minute. Since it doesn’t seem like that project is going to be resuscitated at the moment or any point in the near future, here is the final draft of that article…

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The remarkable potential of stem cells to develop into healthy adult tissue has led many people to view them as a biomedical Wizard of Oz, ready to grant them a healthy new heart or brain on demand—a perception fuelled by fevered media coverage extolling their vast therapeutic potential. But as with the Great and Powerful Oz, misconceptions abound regarding the present capabilities of stem cell-based therapies, and some patients with serious degenerative disorders such as multiple sclerosis (MS) are finding themselves disappointed once they actually peer behind the curtain.

“Most of the patients that come to us ask me to give them stem cells because they want to walk again,” says Antonio Uccelli, a neuroimmunologist performing clinical stem cell research at Italy’s University of Genoa. “Patients are mesmerized by the hope that stem cell treatment is a treatment for regenerating tissue, and it’s difficult to convince them otherwise.”

(more after the jump)

Embryonic stem (ES) cells, which can transform into any cell in the body, may one day offer this potential. ES cells are only slowly making their way into clinical trials, however—in part because ES cell research has been bogged down by strict regulations arising from the lingering debate over the ethics of using material derived from human embryos. The most promising work is instead exploring the treatment of MS with various kinds of adult stem cells, which can develop into a much more limited range of cell types but that nevertheless appear to exert far-reaching effects on both the immune system and the natural repair mechanisms within the central nervous system.

Early studies suggest that treatment with adult stem cells may offer a way to halt the progression of therapy-resistant MS, even if the goal of reversing existing damage still remains over the horizon.

In MS, the immune system attacks the central nervous system. Neurons become stripped of the protective sheaths of myelin that insulates their axons and enables effective signal transmission. Stem cells offer the promise of essentially rebooting the immune system, and thereby eradicating this autoimmune response. There is precedent for this therapeutic approach. More than 25 years ago, Northwestern University immunotherapy expert Richard Burt was inspired by outcomes he observed with leukemia patients undergoing myeloablative treatment—the use of radiation and chemicals to wipe out the body’s capacity for blood cell-production—followed by a transplant of healthy bone marrow. These treatments were spectacularly effective at resetting the immune system. “Patients would come back after transplants and have to be reimmunized for childhood vaccines – measles, mumps, rubella and things like that,” says Burt. “It occurred to me that this is exactly what you want to happen with an autoimmune disease.”

Since then, Burt and others have demonstrated the therapeutic potential of hematopoietic stem cell transplantation (HSCT) for MS and other conditions. In HSCT, blood cell precursors (hematopoietic stem cells)are purified from a patient’s own bone marrow, after which the patient undergoes a ‘conditioning’ chemotherapy regimen that heavily suppresses or even wipes out their defective immune system. These stem cells are then intravenously transplanted back into the patient, whose immunity is thus restored. The results have been remarkable—in many studies, upwards of 60–70% of transplant recipients achieve relief from MS progression that appears to last far beyond the initial treatment1. “In 10 years, we have never seen a renewal of inflammatory disease activity in any of our successfully treated patients,” says Mark Freedman, a neurologist at the University of Ottawa with extensive experience in HSCT clinical trials.

Burt notes that his team has observed not only a halt in deterioration, but, in a number of transplant recipients, actual quantifiable improvements in motor and cognitive function. Some studies indicate that implanted stem cells may facilitate repair by localizing to damaged nervous system tissues; other scientists instead believe that any recovery is simply the result of relief from the immune onslaught. “The signs are quite encouraging that once you stop the immune system in its tracks, the brain’s own repair capacity is able to manifest itself,” says neuroscientist Charles ffrench-Constant of the University of Edinburgh.

Practitioners see HSCT as a powerful way to help patients with aggressive forms of MS that have proven resistant to standard drug regimens. But it’s not a therapy to be taken lightly. Severe side effects include loss of hair and fingernails as well as premature menopause for female patients. “The regimen that we use is completely myeloablative—it’s a standard bone marrow transplant, and it’s no cakewalk,” says Freedman, “but the trade-off is years and years of not needing therapy.” As an alternative, Burt’s group has opted for a more moderate conditioning regimen, which does not completely eradicate the patient’s bone marrow. Work from his team suggests that this gentler approach may reduce the toxic effects of treatment without significantly undermining efficacy2.


Other stem cell types may offer a more palatable option for patients with less aggressive or less advanced disease. Gianvito Martino at the San Raffaele Scientific Institute in Milan,Italy, originally began working in mouse models of MS with neural precursor cells (NPCs), the stem cells that give rise to brain tissue. Martino hoped that the NPCs might penetrate brain lesions and turn into cells called oligodendrocytes, which can directly apply new layers of myelin to damaged cells.

Success was limited. “We didn’t find that those cells differentiate into myelin-forming cells, but they still had apparent curative potential,” Martino explains. “It turned out that they were capable of remaining undifferentiated, and still produce a whole bunch of substances that are neuroprotective.” He and his colleagues termed this the ‘bystander effect’, wherein NPCs secrete signals that quiet the immune system and promote natural processes of neuronal regeneration and remyelination. ffrench-Constant, who has studied myelination extensively, suggests that such strategies for reawakening the brain’s resident stem cells may be the best way to achieve effective repair in many MS patients. He and his colleagues have identified several molecules that might likewise stimulate the differentiation of existing precursor cells into active oligodendrocytes.

NPCs offer the clear advantage of operating in their natural surroundings. “They’re not only in the brain to replace the cells that you lose—they’re also there to keep that microenvironment in a healthy state,” says Martino. Although no clinical trials are currently underway for MS, observers are closely watching a phase I trial being conducted by StemCells Inc. The Palo Alto, California-based company is testing the safety of transplanting fetal tissue-derived NPCs into young children who have a congenital myelin deficiency disorder called PelizaeusMerzbacher disease. “The problem with MS cell therapy is that you’re transplanting cells into an adult nervous system that’s been damaged,” says ffrench-Constant. “I would argue that if these cells don’t myelinate effectively in the developing brains of these children, it’s going to be exceptionally hard to get them to myelinate in the MS-affected adult CNS, where the hurdles are so much higher.”

Even if the NPCs are successful in remyelinating damaged neurons, however, they will always suffer from another problem. NPCs are derived from donated fetal tissue and thus carry a risk of host rejection, which means that immunosuppressant drugs will need to be administered to protect recipients. But there is another, remarkably abundant reservoir of stem cells that may offer many of the same therapeutic benefits as fetal NPCs with the safety and simplicity of autologous transplantation.

Mesenchymal stem cells (MSCs), which normally develop into fat, bone and connective tissue, are typically found in the bone marrow. However, these cells may also exert long-range beneficial effects, and have  been examined as a therapeutic avenue for a wide variety of autoimmune and other conditions. Once injected into MS patients, MSCs  appear to migrate far and wide within the body, homing in on sites of tissue damage and even penetrating the central nervous system. However, their residence there seems to be brief, with therapeutic efficacy arising largely from the same bystander effect observed with NPCs. “Engraftment in the central nervous system is very limited and probably extremely transient,” says Uccelli. “It would be very difficult to believe that this 1-2% of cells [that reach the CNS] can justify the significant and clear evidence of improvement that we observe.”

A number of clinical trials have established the safety of intravenous injections of autologous MSCs for MS. Although formal demonstrations of efficacy are lacking, studies in mouse models have given cause for hope. “If you administer [MSCs] early on, the recovery of the animals tends to be fairly enhanced,” says Freedman. A team led by neuroscientist Robert Miller of Case Western Reserve University in Cleveland, Ohio, has even demonstrated that the administration of human MSCs in the commonly used experimental autoimmune encephalomyelitis (EAE) mouse model can actively promote growth and activation of myelin-repairing oligodendrocyte precursors within the brain3.

MSCs are probably not as good at intense immunosuppression as the HSC treatment, but at least in animal studies, it’s been demonstrated that the ability of MSCs to foster repair is certainly much stronger,” says Uccelli. Although such cell therapy is unlikely to displace first-line immunotherapeutics, it may offer a promising middle-ground therapy before committing to the rigors of HSCT. “There’s no bone marrow suppression or chemo poisons, you’re simply putting in a cell product,” says Freedman, “and since they don’t get rejected, you don’t need anti-rejection medicine.”


Although several clinical trials on stem cell MS therapy have been completed, their small scale and lack of statistical rigor are largely inadequate to make meaningful assessments. “What happens with stem cell studies is that there are three patients here, three patients there and at the end of the day it’s too few to draw any conclusions,” says Martino.

Even with HSCT, which has been successfully performed in several hundred patients worldwide, clinical trials have been limited to individual research centers assessing a few dozen patients. This has led to a confusing patchwork of studies that are virtually impossible to compare with one another. “It’s a dog’s breakfast,” says Freedman. “Different conditioning regimens, different choice of patients, different types of follow-up – it really doesn’t help us to have all these different approaches.”

Many leading MS researchers working with MSCs have banded together to launch the International Mesenchymal Stem Cell Transplantation Study Group, devising a consensus roadmap on how future trials should be conducted4. The resulting guidelines will be implemented in a large-scale, multi-institutional randomized controlled trial with patients in North America and Europe, which consortium members hope to see underway by early 2012. “Each individual group might be doing 15 to 30 patients, but if we have 20 groups doing that and we’re all using the same protocol and all analyzing our data centrally, we’ll have something that’s not exactly equivalent but close to a multi-center study,” says Freedman.

He notes that bone-marrow transplantation researchers have likewise begun to consolidate their efforts, and a similar ‘best practices’ document is on the near horizon. Researchers in the US, Canada and Europe are formulating plans for a large-scale multi-center trial. Burt has already embarked on a phase III randomized controlled trial of HSCT in partnership with researchers in Sweden and Brazil, and has recruited one-third of his 110 study subjects. “The neurologist doing the evaluation of disability has no idea of the treatment the patient has received, and our magnetic resonance imaging data are being analyzed at an MRI reading center in Houston that is also blinded,” says Burt. “I’m very optimistic that a randomized trial will remove a lot of skepticism.”

All the same, it’s easy for hype to outpace the reality, and many MS patients who learn about stem cell therapy from breathless newspaper articles or television news features face letdowns. The clinicians themselves have had to learn some hard lessons in early studies. “In our HSCT clinical trial, we started with patients who had fairly advanced disease: wheelchair-bound or even bedridden,” says Richard Nash, a specialist in immunotherapy at the Fred Hutchinson Cancer Research Center in Seattle,Washington, “and we found that for many of these patients, even after transplantation they are going to continue to get worse.”

Outcomes of subsequent trials have been markedly improved by the recognition that seriously advanced patients have crossed a threshold of nervous system degeneration beyond which anything short of actual neuronal regrowth or replacement is likely to fail. This can be a difficult message for individuals with severe MS to hear. “I find that the only time that patients get mad at me is when we don’t offer the transplant,” says Burt. “It’s hard to get patients to understand that this isn’t going to help them.”

In some cases, this has driven patients to pursue treatment at so-called ‘stem cell clinics’ around the world, where they might pay tens of thousands of dollars to receive injections with cells of dubious provenance in an environment with minimal regulatory oversight. These clinics claim to treat any number of conditions with stem cells, but offer little in the way of peer-reviewed efficacy data. At least one published report has described a patient who developed tumors following one clinic’s transplantation of fetal stem cells5, and Germany recently shut down the X-Cell Center, a clinic where a young patient died from complications following autologous MSC transplantation.

“We are really fighting those clinics,” says Martino, who recently collaborated with colleagues to survey the ‘state of the field’ for clinical stem cell research in MS6. “We prepared this leaflet that anybody can easily download from various MS society websites, where we explained exactly what stage we’re at with the different types of stem cells.”

Most stem cell researchers see cause for optimism, but point out that good science and good medicine require considerable amounts of both time and effort. “The stem cell you use and how you use it will depend on the disease you’re treating as well as the stage, and it’s just beginning,” says Burt. “When I first started I thought I’d have all the answers in five years. But it doesn’t work that way; it takes time.”

1. Mancardi, G. & Saccardi, R. Lancet Neur. 7, 626–636 (2008).
2. Burt, R.K. et al. Lancet Neur. 8, 244–253 (2009).
3. Bai, L. et al. Glia 57, 1192–1203 (2009).
4. Freedman, M.S. et al. Mult. Scler. 16, 503–510 (2010).
5. Amariglio, N. et al. PLoS Med. 6, e1000029 (2009).
6. Martino, G. et al. Nat. Rev. Neurol. 6, 247-255 (2010).

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