The SAGE Encyclopedia of Stem Cell Research. Группа авторов
of MSC therapies for the treatment of ALS, most likely due to the fact that mesenchymal stem cells avoid the ethical and practical issues of embryonic and fetal-derived stem cells by being easily derived stem cells from adult connective tissues.
Italy
The first of such clinical trials utilizing MSC therapy to treat ALS was done by the Mazzini group at the San Giovanni Bosco Hospital in Torino, Italy, in 2003. Letizia Mazzini et al. isolated MSCs from allogeneic ALS patient bone marrow aspirates, and in their initial clinical study, seven ALS patients received transplantation with these MSCs into their thoracic spinal cord with varying numbers of injection sites and cell numbers. Patients were observed more than four years after their surgeries, and while there was no observed clinical or functional improvement in these patients, no serious side effects or detriment to neurological function was reported over the entire follow-up period. However, due to the small number of patients tested and inconsistency in the number of MSCs administered per patient, there was no definitive conclusion as to whether implantation of MSCs into ALS patients was undeniably safe and well tolerated.
To address these issues, Mazzini et al. performed a second Phase I clinical trial with a group of 19 ALS patients and observed these patients for up to 9 years after surgery using the same procedure and same cell line. Again, while no significant functional improvement or slowed progression of disease was observed in these groups, there were still no major side effects after receiving the transplantation, and the treatment was deemed to be overall safe and well tolerated with no immediate or long-term harmful consequences. The only international group to study neural stem cell transplantation in ALS patients is the Vescovi group in Terni, Italy. Their study aims to deliver human neural stem cells into the spinal cord of 18 ALS patients in a Phase I clinical trial (NCT01640067). The study is currently ongoing with no results published.
Israel
BrainStorm Cellular Therapeutics in recent years developed human bone marrow stromal-derived MSCs that are differentiated into specialized neuron-supporting cells to secrete neurotrophic factors, named MSC-NTF and trademarked as NurOwnTM. These cells are known to express the markers of neural support cells such as glial fibrillary acidic protein (GFAP) and glutamine synthase, as well as to secrete neurotrophic factors such as brain-derived neurotrophic factor (BDNF), glial cell line–derived neurotrophic factor (GDNF), and insulin-like growth factor-1.
Hadassah Medical Organizations in Israel in 2010 collaborated with BrainStorm Therapeutics to start a Phase I/II open-safety clinical trial using the intrathecal and intravenous administration of NurOwn cells into patients with ALS. The study ultimately showed that the intravenous and intrathecal injection of these cells was safe via lumbar puncture or intravenously. (Another Phase I/II open-label clinical trial by the same group evaluated the safety, tolerability, and therapeutic effects of transplanting the NurOwn cells into ALS patients; 12 patients were transplanted intrathecally or intramuscularly. Another Phase IIa dose-escalation trial was also started in 2013 in which another 12 ALS patients were administered NurOwn cells with both intramuscular and intrathecal injections with increasing doses. Both of these studies are still ongoing with no published results as of April 2014 (NCT01777646, NCT01051882).
Mexico
In Mexico at the Hospital San José Tecnológico de Monterrey, the method of transplanting blood-derived stem cells into the frontal cortex of ALS patients to target upper motor neurons was studied in 2005 to 2006 (NCT01933321). The study determined that the transplantation of blood-derived stem cells into the frontal cortex was well tolerated and safe. However, as detailed by the ALSUntangled group in 2010, due to variable treatment dosing between patients, tremendous variability in data, and a dearth of objective measures of safety or integrity of the transplants, these conclusions are questionable.
Spain
At the Universidad de Murcia in Murcia, Spain, Jimenez et al. studied the intraspinal infusion of autologous bone marrow mononuclear cells (BMNCs) in patients with ALS. BMNCs contain a broader range of cells than bone marrow–derived MSCs (NCT01254539, NCT00855400). BMNCs are the isolated mononuclear fraction of the bone marrow aspirate, which includes B cells, T cells, and monocytes of the immune system, in addition to MSCs and HSCs. In their Phase I trial, 11 patients were studied with no acceleration in disease progression, and spinal cord analysis showed a greater number of motoneurons in treated segments compared to untreated segments. Due to the safety and lack of significant adverse events in the treated population, a further Phase I/II study was initiated in 2010 and is ongoing with no published results as of April 2014.
Iran
Hamid Gourabi et al. at the Royan Institute in Iran are taking a three-pronged approach by having three separate trials studying the efficacy and safety of transplantation of MSC in patients with ALS intravenously, intraventricularly, and intrathecally (NCT01759797, NCT01759784, NCT01771640). So far, only one of these three studies has been completed and no results have been published, with also very little description on their methods to date.
Korea and China
Finally, both China and Korea also have clinical trials ongoing to study the effects of MSC transplantation in ALS patients. An et al. at the General Hospital of Chinese Armed Police Forces are currently studying the use of umbilical cord MSCs in ALS patients (NCT01494480), while Corestem Inc., in collaboration with Kim et al. at the Hanyang University Seoul Hospital, is studying the safety of transplanting HLA-haplo matched bone marrow–derived stem cells (HYNR-CS-Allo inj) via intrathecal injection (NCT01758510, NCT01363401). Again, both of these studies are ongoing with no published results to date.
Leslie Suen
Pablo Avalos
Doniel Drazin
Cedars-Sinai Medical Center
See Also: Clinical Trials, Ethics of; Clinical Trials Outside the United States; Clinical Trials, U.S.: Amyotrophic Lateral Sclerosis.
Further Readings
Hench, Larry L., Julian R. Jones, and Michael B. Fenn, eds. New Materials and Technologies for Healthcare. London: Imperial College Press, 2012.
Mazzini, L., et al. “Mesenchymal Stem Cell Transplantation in Amyotrophic Lateral Sclerosis: A Phase I Clinical Trial.” Experimental Neurology, v.223/1 (2010).
Svendsen, Clive, et al. “The Past, Present, and Future of Stem Cell Clinical Trials for ALS.” Experimental Neurology (in press).
Clinical Trials Outside the United States: Cerebral Palsy
Clinical Trials Outside the United States: Cerebral Palsy
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Clinical Trials Outside the United States: Cerebral Palsy
Cerebral palsy (CP) is the broad heterogeneous term used for a group of permanent, nonprogressive movement disorders that cause varying degrees of physical disability that typically involve body movement variations. Individuals with cerebral palsy also may experience variations in sensations, communication deficits, difficulties with depth perception, cognitive alterations, learning disabilities, behavioral problems, and seizure disorders. There are subtypes of CP that are characterized by the type of impairment. The different types include spastic, ataxic, athetoid/dyskinetic, and mixed. The majority of individuals have spastic CP. Cerebral palsy is the most commonly occurring motor disability in childhood.
CP is caused by a variety of factors, including infection in pregnancy, hypoxia during birth, severe neonatal jaundice, Rh incompatibility, or genetic factors. CP is more common in male infants and African Americans. In the United States, 800,000 individuals are diagnosed with CP, with an additional 10,000 babies diagnosed annually. Cerebral palsy