Bone Marrow Stem Cell Treatment Plus Immunosuppression are Superior to Immunosuppression Alone in Multiple Sclerosis Patients

Multiple Sclerosis (MS) is a debilitating autoimmune disease in which the immune system attacks elements of the central nervous system. There are different types of MS, but more progressive cases can leave patients unable to walk and may require rather extreme immunosuppressive treatments that can predispose a patient to illness and cancer.

However, a new study that was published in the journal Neurology has shown that stem cell transplantation could be a more effective therapy in severe cases of multiple sclerosis (MS) than the drug mitoxantrone.

Mitoxanthone is a “type II topoisomerase inhibitor” that disrupts DNA synthesis and DNA repair by inserting between the bases in DNA. Mitoxanthone can cause nausea, vomiting, hair loss, heart damage, and suppression of the immune system. Some side effects may have delayed onset. Heart damage (cardiomyopathy) is a particularly concerning effect with this drug, since it is irreversible. Therefore, because of the risk of cardiomyopathy, mitoxantrone carries a limit on the cumulative lifetime dose, which is based on the body surface area of patients.


Because MS is an immune-mediated disorder, and because immune cells are made by stem cells in the bone marrow, bone marrow transplants (hematopoietic stem cell transplantation), which are routinely used in the treatment of leukemia and lymphoma, are being considered as a treatment for MS.

A clinical trial conducted by Giovanni Mancardi from the University of Genova, Italy designed a randomized phase II clinical trial study that included 21 MS patients, whose average age was 36 and whose disability due to the disease had worsened in the previous year despite the fact that the patients were under conventional medication treatment. The average disability level of the participants was represented by the need of a crutch or cane to walk. The goal of the study was to determine the efficacy of intense immunosuppression followed by either a bone marrow transplant with the patient’s own bone marrow, or mitoxantrone (MTX) in MS disease activity.

Giovanni Mancardi
Giovanni Mancardi

All participants in this clinical trial received immune-suppressive medication. MTX was given to 12 of the patients while the remaining 9 received hematopoietic stem cells harvested from their own bone marrow. After treatment with MTX, the stem cells were intravenously reintroduced into their donors and the stem cells migrated back to the bone marrow where they generated new immune cells. All participants were followed-up for a period of up to four years after their treatment.

“This process appears to reset the immune system,” said the lead study author Dr. Giovanni Mancardi. “With these results, we can speculate that stem cell treatment may profoundly affect the course of the disease.”

Mancardi and his team found that treatment of MS patients with robust immunosuppression followed by stem cell treatment resulted in a significantly higher decrease in disease progression in comparison with MTX treatment alone. MS patients under stem cell treatment reduced the number of new areas of brain damage (T2 lesions) by 79% compared to patients under MTX treatment. Another type of lesion seen in MS patients – gadolinium-enhancing lesions – were not detected in patients under stem cell treatment during the study, whereas 56% of patients receiving MTX exhibited at least one new gadolinium-enhancing lesion.

Mancardi and his team concluded that an intense immunosuppression followed by autologous hematopoietic stem cell transplantation is more efficient than MTX to reduce MS activity in severe cases.

“More research is needed with larger numbers of patients who are randomized to receive either the stem cell transplant or an approved therapy, but it’s very exciting to see that this treatment may be so superior to a current treatment for people with severe MS that is not responding well to standard treatments,” concluded study author Dr. Mancardi.

Gene Discoveered That Drives Fertility in Male Mice

Workers in the laboratory of Richard Freiman, associate professor of medical science at Brown University have discovered a specific gene in human males that seems to be essential to sperm production later in life.

A paper published in the journal Stem Cells details how the loss of a protein called TAF4b in male mice causes premature infertility. According to Freiman, mutations that prevent the continuous production of TAF4b leave mice incapable of sustaining spermatogenesis after only a few months of sexual maturity.

This study began when Freiman’s team discovered that TAF4b was expressed at high levels in the ovaries and the testes. Later, Freiman and his colleagues used homologous recombination to specifically modify the TAF4b gene. Freiman explained that homologous recombination can “knock specific genes out of the mouse genome,” after which you can “examine the mice that are born and see what function the gene serves in normal development.” Such experiments showed that male mice whose TAF4b gene was synthetically modified so that it expressed TAF4b initially, but did not sustain its expression were only fertile for a month or two, whereas mice with intact TAF4b remained fertile for several years.

“Cells that are involved in initial fertility are different than cells involved in subsequent rounds of sperm production. The first set undergoes meiosis and become sperm by a direct route, but the other set develops into precursor cells that become stem cells,” Freiman said. “What we hypothesized about our mice is that they’re able to go through this initial round of spermatogenesis, but they can’t make the stem cell population, so they can’t set themselves up for long-term fertility,” he added.

Since humans have a TAF4b gene that is very similar to the mouse gene, the results of Freiman’s laboratory might be applicable to human fertility, said Eric Gustafson, a postdoctoral research fellow in Freiman’s laboratory and first author of the paper.

These results interact with another study that was published last year that examined a population of four infertile brothers in eastern Turkey; each of whom each had a homozygous mutation in their TAF4b gene similar to the one created in the mice. According to Gustafson, these men had very low or no sperm counts. “So we think these genes have many similar, if not identical functions in humans. What we learn about in the mouse gene may be used to address or diagnose reproductive defects in humans as well,” he added.

With couples having children later and later in life, this study has important implications for family planning. “If we could learn how this process is regulated normally, clinicians might be able to devise better strategies to either monitor or even intervene with cases of infertility,” said Freiman. To give an example, Freiman suggested that if scientists could detect the mutation in teenage boys early on, then doctors could freeze their patients’ sperm for later in life.

The study also has important outcomes in terms of stem cell research, said Professor of Biology Gary Wessel, who was not involved in the study. “This research shows us that this particular transcription factor, TAF4b, is involved in the transcription process involved in maintaining the stem cell itself,” Wessel said. “As a consequence, it now gives the investigators a more careful view of what stem cell decisions are like,” he added.

The study’s results are relevant to all stem cell research, Wessel said. “Everything in biology is connected. If you make any kind of breakthrough, it’s going to have ripple effects throughout the entire discipline.”

How does TAF4b affect fertility? That’s the next goal of Freiman’s research. Freiman said. “We now know that TAF4b performs this function, but we don’t know how it does it,” he added. “Once we figure that out, it might reveal new areas of intervention for fertility preservation.”