Editors' ChoiceNeurodegenerative Disease

Stemming the tide of ALS

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Science Translational Medicine  27 Jan 2016:
Vol. 8, Issue 323, pp. 323ec15
DOI: 10.1126/scitranslmed.aaf0867

Neurotrophic factors (NTFs) are protective for motor neurons. Despite this, clinical trials of peripherally administered NTFs in patients with amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disease that is invariably fatal, have failed to show benefit. Mesenchymal stem cells (MSCs) are protective in animal models of neurodegenerative diseases, including ALS. One possibility for the protective effects of MSCs could be that these cells produce NTFs. In a proof-of-concept clinical study, Petrou and colleagues show that autologous transplantation of MSCs, engineered to produce NTFs, appears to be safe and may slow disease progression in ALS patients.

These investigators performed a single-dose safety study followed by an open label dose-ascending study in clinically definite or probable ALS patients between 20 and 75 years of age at the Hadassah Medical Center in Jerusalem, Israel. Each study consisted of a 3 month run-in period, in which rates of disease progression were determined; a single autologous MSC transplant; and 6 months of follow up. MSCs were isolated from bone marrow aspirates from ALS patients and engineered in culture to upregulate production of NTFs (MSC-NTFs). The primary outcome of the study was safety. Secondary measures included changes in the average monthly slope of decline pre and post treatment using the ALS Functional Rating Scale-Revised (ALSFRS-R), forced vital capacity (FVC), biceps compound muscle action potential amplitude, and MRI arm muscle volume. Overall, they found no serious adverse events after MSC transplantation. The most common side effects were transient and related to MSC administration. These included headache, fever, back/leg pain, vomiting, and stiffness. A post hoc analysis of all patients receiving either intrathecal or intramuscular plus intrathecal MSC-NTF transplantation (n=15) found: (i) a slowing in loss of respiratory function (p = 0.04) and a trend towards benefit in other secondary measures; and (ii) 87% of patients showed at least a 25% improvement on either the ALSFRS-R scale or in the FVC slope of decline.

The authors conclude that intrathecal administration of MSC-NTFs may be more effective than peripheral administration of NTFs alone due to better delivery to the central nervous system. Limitations of the study include the lack of a control group, the small number of patients, and the short duration of follow up. A phase 2 randomized control clinical trial of MSC-NTFs in ALS patients is ongoing.

P. Petrou et al., Safety and clinical effects of mesenchymal stem cells secreting neurotrophic factor transplantation in patients with amyotrophic lateral sclerosis: Results of phase 1/2 and 2a clinical trials. JAMA Neurol. 10.1001/jamaneurol.2015.4321 (2016). [Abstract]

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