Neural and glial progenitor transplantation as a neuroprotective strategy for Amyotrophic Lateral Sclerosis (ALS)

ALS is a neurodegenerative disease with a prevalence rate of up to 7.4/100,000 and the overall risk of developing ALS over a lifetime is 1:400. Most patients die from respiratory failure following a course of progressive weakness. To date, only one traditional pharmaceutical agent-riluzole, has been shown to afford a benefit on survival but numerous pharmaceutical interventions have been studied in preclinical models of ALS without subsequent translation to patient efficacy. Despite the relative selectivity of motor neuron cell death, animal and tissue culture models of familial ALS suggest that non-neuronal cells significantly contribute to neuronal dysfunction and death. Early efforts to transplant stem cells had focused on motor neuron replacement. More practically for this aggressive neurodegenerative disease, recent studies, preclinical efforts, and early clinical trials have focused on the transplantation of neural stem cells, mesenchymal stem cells, or glial progenitors. Using transgenic mouse or rat models of ALS, a number of studies have shown neuroprotection through a variety of different mechanisms that have included neurotrophic factor secretion, glutamate transporter regulation, and modulation of neuroinflammation, among others. However, given that cell replacement could involve a number of biologically relevant factors, identifying the key pathway(s) that may contribute to neuroprotection remains a challenge. Nevertheless, given the abundant data supporting the interplay between non-neuronal cell types and motor neuron disease propagation, the replacement of disease-carrying host cells by normal cells may be sufficient to confer neuroprotection. Key preclinical issues that currently are being addressed include the most appropriate methods and routes for delivery of cells to disease-relevant regions of the neuraxis, cell survival and migration, and tracking the cells following transplantation. Central to the initial development of stem cell transplantation into patients with ALS is the demonstration that transplanted cells lack tumorigenicity and have the appropriate biodistribution to ensure the safety of ALS patients receiving these therapies. Here, we review preclinical and clinical studies focusing on the transplantation of neural and glial progenitor cells as a promising neuroprotective therapy for ALS. The rationale for stem cell transplantation for neuroprotection, proof-of-concept animal studies, and current challenges facing translation of these therapies to the clinic is presented. Lastly, we discuss advancements on the horizon including induced pluripotent stem cell technology and developments for cellular tracking and detection post-transplantation. With the safe completion of the first-in-human Phase I clinical trial for intraspinal stem cell transplantation for ALS in the United States, the time is ripe for stem cell therapies to be translated to the clinic and excitingly, evaluated for neuroprotection for ALS. This article is part of a Special Issue entitled SI: Neuroprotection.