Pluripotent engineered stem cell-derived neural stem cells improve spinal muscular atrophy phenotype in mice

Spinal muscular atrophy (SMA), a motor neuron disease and the most common genetic causes of infant mortality, has no cure. Stem cell transplantation is a potential therapeutic strategy for SMA. We recently described that primary neural stem cell (NSC) transplantation can ameliorate the disease phenotype in a mouse model of SMA, but this primary source has limited translational value. Here, we show that pluripotent stem cells from embryonic stem cells (ESCs) show the same potential therapeutic effects as those derived from spinal cord and offer great promise as an unlimited source of NSCs for transplantation. We investigate also the therapeutic potential of NSCs derived from a genetically engineered murine embryonic stem cells (ES) lineage (OSG). These cells drug-selectable ESC line yielded the greatest improvements. We found that ESC-derived NSCs and OSG-derived NSCs can differentiate into motor neurons in vitro and in vivo. In addition, following their intrathecal transplantation into SMA mice, the NSCs, like those derived from spinal cord, survived and migrated to appropriate areas, ameliorated behavioural endpoints and lifespan, and exhibited neuroprotective capability in SMA mice. Any side effect such as teratoma formation was observed. To define the molecular mechanisms through which ES-NSCs may ameliorate the SMA phenotype, we analyzed by ELISA the levels of neurotrophins. ES-NSC transplantation positively affected the SMA disease phenotype. Our results suggest translational potential for the use of pluripotent cells in NSC-mediated therapies and highlight potential safety improvements and benefits of drug selection for neuroepithelial cells.