Neurotrophic factors (NTFs) are essential growth factor proteins that support the development, survival, and proper function of neurons. We have developed muscle progenitor cell (MPC) populations expressing brain-derived neurotrophic factor (BDNF), glial-derived neurotrophic factor (GDNF), vascular endothelial growth factor (VEGF), or insulin-like growth factor-1 (IGF-1). Transplantation of a mixture of such MPC populations (MPC-MIX) into the hind legs of SOD1 G93A transgenic mice (SOD1 mice), the commonly used model of ALS, delayed the onset of disease symptoms by 30 days and prolonged the average lifespan by 13 days. Treated mice also showed a decrease in the degeneration of neuromuscular junction and an increase in axonal survival. Cellular mechanism assays suggest a synergistic rescue effect of NTFs that involves the AKT and BAD signaling pathways. The results suggest that long-term delivery of a mixture of several NTFs by the transplantation of engineered MPC has a beneficial effect in the ALS mouse model.