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    • No effective therapies are available

    2018-10-20

    No effective therapies are available for motor neuron diseases, including SMARD1. Neural stem cell (NSC) transplantation represents a possible therapeutic strategy for ameliorating the neurological phenotype by multiple mechanisms, including neuroprotection and cell replacement of different CNS nuciferine (Donnelly et al., 2012). These positive effects of stem cell transplantation (neural and nonneural cells) have been demonstrated in earlier studies by us and other groups (Corti et al., 2006, 2008, 2009, 2010, 2012; Donnelly et al., 2012). As our work has shown, NSC and neuronal precursor transplantation in animal models improves the phenotype of motor neuron diseases, including SMA, SMARD1, and amyotrophic lateral sclerosis (ALS) (Corti et al., 2006, 2008, 2009, 2010, 2012). In fact, we described that primary murine NSC transplantation can improve the disease phenotype in a SMARD1 mouse model (Corti et al., 2006). Furthermore, a phase I safety trial of direct intraspinal transplantation of NSCs into patients with ALS is in progress, approved by the US Food and Drug Administration (Boulis et al., 2011). Recently, Teng et al. has shown the effectiveness of transplanted NSCs in slowing disease and prolonging survival in ALS mice, rescuing the phenotype completely in 25% of cases (survival increased to more than a year compared to 4 months in untreated animals) (Teng et al., 2012), but 40% of transplanted animals still show only a mild survival improvement. These data represent an unprecedented success in this ALS model because pharmacological/molecular treatments have up to now not produced such remarkably successful therapeutic outcomes. One caveat is represented by the observed variability that might have to do with some variation in the neuroprotective features of transplanted cells and the fact that our understanding of the variables that are critical to therapeutic success remains incomplete. Other persistent limitations include that the source of human NSCs, primary CNS tissue (fetal brain), is limited. The reprogramming of adult somatic cells into induced pluripotent stem cells (iPSCs) can provide an unlimited source of NSCs for therapeutic use (Ito et al., 2012). Recently, we described that transplantation of a specific NSC population delayed disease progression and extended the life span of ALS mice (Nizzardo et al., 2013). In the present study, we investigated the therapeutic potential of transplanting human iPSC-derived NSCs into the spinal cord of nmd mice, which demonstrated that the engraftment capacity of these cells is associated with an amelioration of the SMARD1 disease phenotype. NSCs are especially remarkable because they can promote cell survival and axonal growth of murine and human SMARD1 motor neurons, which is attributable to the fact that NSCs inhibit both GSK-3 and HGK kinases. This capacity emphasizes that iPSC-derived NSC-mediated therapies hold promising translational potential in motor neuron disorders.
    Results
    Discussion Increasing preclinical evidence suggests that NSC transplantation can exert a therapeutic effect on motor neuron disease phenotypes (Donnelly et al., 2012). This positive effect is likely related to multiple mechanisms including not only replacement of different CNS cell populations but also neuroprotection of host motor neurons by different factors produced by donor cells (Boulis et al., 2011). Previously, we reported that primary murine NSC transplantation can improve the disease phenotype in a SMARD1 mouse model (Corti et al., 2006). These data demonstrated the therapeutic potential of NSC transplantation for this disease. In the present study, we demonstrated that transplanted human iPSC-derived NSCs can engraft into the SMARD1 spinal cord, also in the anterior horns, the areas of active degeneration, after which they differentiate into the three major neuroectodermal lineages and generate motor-neuron-like cells, even if in a small proportion. Transplantation of iPSC-derived NSCs significantly improved the neurological phenotype and survival of nmd mice. Indeed, this transplantation significantly correlated with a reduced pathology of the spinal cord and protection of endogenous motor neurons. These results build upon the findings from our previous work in regards to translational possibilities: pluripotent cell sources, particularly iPSCs, are much more readily available and accessible than CNS primary-derived NSCs.