Results from the experimental autoimmune encephalitis (EAE) mouse model of MS provided the rationale for the therapy, showing that injected cells can migrate to the site of inflammation and aid in remyelination.
THE INTRAVENOUS ROUTE
Dr. Cohen led a study in which 24 MS patients received a single intravenous infusion of 1-2 million cryopreserved autologous MSCs. Patients were followed for the two months it took for the withdrawn cells to be expanded, and then for six months after treatment. The last patient completed follow-up in January 2014.
Ten patients had relapsing-remitting MS and 14 had the secondary progressive form of the disease. The mean disease duration was about 14 years, and 12 patients were receiving disease-modifying therapy. One quarter of the group had gadolinium-enhancing lesions at the start of the trial.
Dr. Cohen noted that while there was “noticeable variability” in the yield of cells from the aspirate, as well as in growth and final yield, there was “no apparent correlation with patient demographics, MS diagnosis, clinical features, or other treatments.”
Feasibility and safety were the primary outcomes for the phase 1 trial. “Overall, we encountered no significant safety issues,” he said. “There were, in fact, very few if any side effects, and certainly no serious or severe adverse events.” He added that the researchers observed no autoimmune phenomena, and there was also no evidence of paradoxical disease activation, a theoretical concern based on a past study showing an increase in Th17 responses under some cell culture conditions when human MSCs were added.
There was no indication of any increase in lesions, “but also no apparent benefit,” Dr. Cohen said. The researchers observed no change in either median or mean disability scores, although a few patients showed some improvement. “While there was no evidence of disease activation, there was also no evidence of benefit on any of these measures for patients as a group,” he said.
The results of the study “support the feasibility, safety, and tolerability” of intravenously administered MSCs for MS, Dr. Cohen said. But “there are a number of issues that need to be resolved before moving to phase 2 [trials],” including dose, number of treatments, whether cells from a disease-free donor might offer advantages, and whether cells should be cryopreserved, as they were in this study, or injected fresh from the expansion culture.
Reflecting on the methodology and results, Dr. Cohen said that if he could repeat the study, he would look at higher stem cell doses and consider using “fresh” cells, based on recent studies suggesting that newly thawed cells are not fully functional.
THE INTRATHECAL ROUTE
Saud A. Sadiq, MD, FAAN, director of the Tisch MS Research Center of New York, is leading an ongoing study of infusion of autologous MSCs, which differs in several potentially important ways from Dr. Cohen's study. The stem cells in his study are infused intrathecally, they are fresh — not cryopreserved — and patients receive three doses, not one.
In addition, the MSCs are treated during the expansion process with growth factors to convert them to neural progenitor cells. “This reduces their lipidogenic and osteogenic potential, which had been thought to be a risk,” Dr. Sadiq explained.
The multiple dosing was based on preclinical work in the EAE mouse. “We found that a single dose had very little effect while multiple doses led to a sustained clinical benefit,” with improvement in the EAE clinical score and a decrease in demyelination and T-cell infiltration, he noted.
An unpublished initial clinical study in six patients, some of whom are now in their ninth year of follow-up, suggested the treatment was safe, with no formation of tumors or ectopic tissue.
That led to the current trial, in which 20 patients will receive three injections of up to 10 million cells each, spaced three months apart. So far, three patients have received at least one infusion; one patient had received two infusions at the time of the presentation. Dr. Sadiq said that so far there have been no adverse effects, except for spinal headache.
“We think that if there are any benefits, it is probably based on the growth factors that the cells secrete, the local immunoregulatory effects they would have, and migration to sites of injury,” Dr. Sadiq said. “We don't think there is a direct remyelination by these cells.”
Dr. Cohen concurred. “We don't think these cells directly replace cells in the nervous system,” he said. “If they promote repair, it is by enhancing intrinsic repair mechanisms.”
Mark S. Freedman, MD, FAAN, a professor of medicine and director of the Multiple Sclerosis Research Unit at the University of Ottawa in Canada, said he was “encouraged” by the results but is looking forward to larger trials that can assess efficacy.
“Safety has been demonstrated, but we need to demonstrate a biological effect in humans,” he said. “The challenge is that there is currently no marker available to track the long-term migration of infused cells, and thus no way to know if any change in remyelination can be directly attributed to the treatment. Without that, future trials will examine the more easily detectable anti-inflammatory effects of the therapy.
“There are lots of drugs that can turn down inflammation, but that's what we'll be looking for,” he added. “If we are able to demonstrate one biological effect, presumably all the other effects will also be on the table.”
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•. Harris VK, Farouqi R, Vyshkina T, Saddiqu S. Characterization of autologous mesenchymal stem cell-derived neural progenitors as a feasible source of stem cells for central nervous system applications in multiple sclerosis. Stem Cells Transl Med
2012;1(7):536–547. Epub 2012 Jun 28.
•. Harris VK, Yan QJ, Vshinka T, et al. Clinical and pathological effects of intrathecal injection of mesenchymal stem cell-derived neural progenitors in an experimental model of multiple sclerosis. J Neurol Sci
2012;313(1–2):167–77. Epub 2011 Oct 1.
•. More about the stem cell trial underway by Saud Sadiq, MD
© 2014 American Academy of Neurology
•. More about the stem cell trial underway by Jeffrey A. Cohen, MD
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