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Clinical Trials Outside the United States: Amyotrophic Lateral Sclerosis

Clinical Trials Outside the United States: Amyotrophic Lateral Sclerosis

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Clinical Trials Outside the United States: Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is a devastating neurodegenerative disorder characterized by rapidly progressive weakness due to degeneration of motor neurons in the brain cortex, brain stem, and spinal cord. Treatments for ALS have been limited due to the diverse nature and unknown etiology of the disease. Riluzole (Rilutek) is the only FDA-approved treatment known to improve survival in ALS patients, but only by a span of several months. Much of this difficulty in finding treatment relates to the various etiologies and heterogeneity that exist within ALS. In recent years, much interest has been divested into the use of human pluripotent stem cells for the treatment of ALS. While the initial idea was to use the pluripotent stem cells to replace lost motor neurons in ALS, this idea proved impractical given the long-distance projections and complicated functional connections that these new stem cell motor neurons would need to make in order to replace their predecessors.

Another more feasible option would be to use the pluripotent stem cells to re-create support cells in the neuronal environment, nourishing already existing motor neurons to thrive and possibly detoxifying the environment to prevent further cell death. Support cell types in the nervous system can be generated from other tissues such as mesenchymal stem cells (MSCs) and neural stem cells (NSCs). Mesenchymal stem cells can be derived from existing connective tissue such as bone marrow, cartilage cells, and fat cells, as well as from umbilical cord tissue. Neural stem cells can be derived from the fetal brain. Preclinical studies have shown the ability to use MSCs and NSCs to generate functional support cells to improve motor neuron survival in ALS models. The hope is to determine the safety and efficacy of using mesenchymal and neural stem cell transplantation into patients with ALS and maximize the therapeutic benefit achievable with such treatment.

Most of the current clinical research using an MSC or NSC model for the treatment of ALS is done outside the United States, in countries like Italy, Iran, Israel, and Mexico. The majority of these countries focus on the use 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).