29 October 2010. Amidst all the promise of stem cell technology, there is also a heaping share of worry. The cells could go rogue, spreading to unintended places and morphing into cancer cells. A paper in the October Archives of Neurology now provides a small measure of comfort: Researchers from the Hadassah-Hebrew University Hospital in Jerusalem, Israel, report that mesenchymal stem cell grafts caused no trouble in people with amyotrophic lateral sclerosis (ALS) or multiple sclerosis (MS).
“These studies are trying to find new ways to use stem cells to deliver therapies to the spinal cord,” said Anthony Windebank of the Mayo Clinic in Rochester, Minnesota. He was not involved in the report, but is doing similar research. Mesenchymal stem cells (MSCs) are part of the body’s response to injury. “They produce literally dozens of tissue-protective factors,” Windebank says. So once they home in on inflamed tissues, they act like cellular pharmacists, doling out neurotrophic factors and immunomodulators that could protect cells. This approach, using MSCs to deliver protective molecules, is different from attempts using neural stem cells, which might actually replace degenerated tissues (see ARF related news story and Xu et al., 2006). However, the study authors note that using certain cell-culture tricks, it is possible to turn MSCs into neuron- and glia-like cells (Bossolasco et al., 2005). MSCs are also advantageous because they are easily harvested from bone marrow and can be expanded for autologous transplantation.
The study, led by Dimitrios Karussis, was a Phase 1/2 open safety trial for 15 people with MS and 19 with ALS. Karussis and colleagues already showed that MSCs home to inflamed areas in the CNS and subdue inflammation in a mouse model of MS (Kassis et al., 2008). MSC transplantation also improved survival in ALS model mice (Morita et al., 2008).
The current study supports a handful of others indicating that MSCs are safe for human injection in ALS (Mazzini et al., 2006; Mazzini et al., 2010) and MS (Mohyeddin Bonab et al., 2007). Other safety trials for MSCs in MS are running in Spain—one sponsored by the Fundacion Progreso y Salud and another by the Hospital Clinic of Barcelona—as well as at the U.K.’s University of Cambridge and the Cleveland Clinic in Ohio. Windebank and colleagues at the Mayo Clinic are examining MSC safety in ALS. The Jaslok Hospital and Research Centre, in Mumbai, India, is studying MSC safety in Parkinson’s disease. Many other trials are ongoing for stroke and other conditions.
Karussis and colleagues collected cells from each participant’s bone marrow and cultured MSCs in the lab. Then, they returned the expanded, purified MSCs to the people via intrathecal injections; some participants also received MSCs intravenously. They followed the subjects for at least six months, and some as far as 25 months.
The study authors noticed no problematic side effects. The main complaints were fever or headache from the lumbar puncture, which subsided within a week. Using magnetic resonance imaging (MRI), doctors checked participants for any unexpected pathology. There was nothing unusual to note.
To do any good, MSCs have to find the places where they are needed. In nine of the participants, the researchers tagged their expanded MSCs with iron oxide nanoparticles. Then, the scientists used MRI to examine where the cells ended up. They observed labeled cells in the nerve roots, meninges, and parenchyma of the spinal cord, indicating the transplants migrated away from the injection site.
One hope for MSCs is that they could downgrade harmful inflammation and promote protective immune responses. In 12 participants, who received both intrathecal and intravenous MSCs, the scientists collected peripheral blood to examine immune activity. They found that following the MSC treatment, 72 percent more regulatory CD4+ CD25+ T cells cruised the veins. However, the population of activated CD40 cells—which can promote inflammation—dropped by half. “Although it is difficult to estimate the clinical relevance of these immunological effects, changes of that magnitude are stronger than those induced by the conventional immunomodulatory medications,” the authors write.
These results are most relevant to MS, wrote Letizia Mazzini of Eastern Piedmont University in Novara, Italy, in an e-mail to ARF. Autoimmunity is the cause of the disease, so immunomodulation is an appealing strategy. In ALS, the role of the immune system is murkier, and may include both beneficial effects from protective T cells and harmful effects from inflammation (see ARF related news story).
Although the primary study endpoint was safety, the authors also looked for any improvement or plateau in disease progress. For people with MS, they used the Expanded Disability Status Scale, which quantifies how much of the body is disabled. On average, the scores in the MS group improved from 6.7 to 5.9 within six months. In ALS cases, the researchers used the ALS-Functional Rating Scale, a measure of how well people can complete daily tasks such as speaking and walking. There was no significant change in the ALS-FRS.
“The clinical conclusions seem to be early,” Mazzini commented. “The small sample of patients, the lack of a control group, and the great inter-subjects variability of the diseases do not allow us to conclude anything about the efficacy.”
The Hadassah team plans a future study of MSCs in people with ALS; they will examine several characteristics of the disease including muscle bulk and forced vital capacity.—Amber Dance.
Karussis D, Karageorgiou C, Vakin-Dembinsky A, Gowda-Kurkalli B, Gomori JM, Kassis I, Bulte JWM, Petrou P, Ben-Hur T, Abramsky O, Slavin S. Safety and immunological effects of mesenchymal stem cell transplantation in patients with multiple sclerosis and amyotrophic lateral sclerosis. Arch Neurol. 2010 Oct;67(10):1187-94. Abstract