Developing specific motoneuron subtypes from embryonic stem cells, and induced pluripotent stem cells, to treat neuromuscular disorders and paralysis due to injury.

Motor neuron diseases such as amyotrophic lateral sclerosis (ALS) are devastating neurodegenerative disorders caused by the selective loss of motoneurons. As spinal motoneurons die, muscles become progressively weaker, to the point of complete paralysis, due to muscle denervation. Patients succumb to the disease when they lose the ability to control voluntary and rhythmic movements such as breathing. There is currently no cure for ALS. Motoneurons also die in patientssuffering from a spinal cord injury (SCI). Fracture and/or dislocation of the vertebrae produce massive damage to the delicate underlying tissue of the spinal cord resulting in the death of motoneurons innervating skeletal muscles. Motoneurons do not regenerate. Consequently the only means to restore function to muscles denervated by the loss of motoneurons resulting from ALS or SCI is to replace them with healthy motoneurons. The aim of this proposal is to first develop different subtypes of motoneurons from mouse embryonic stem (ES) cells and then show that they are capable of restoring muscle function when transplanted near paralyzed muscles. We aim to show that different subtypes of motoneurons can be generated from mouse ES cells that normally innervate leg or postural muscles. We will then show that muscle recovery is better when the paralyzed muscle is reinnervated by their appropriate subtype of motoneuron (e.g. paralyzed leg muscles will recover better when reinnervated by leg motoneurons). Finally, we will determine whether induced pluripotent stem cells (iPS) cells have the same capacity to make different subtypes of motoneurons and restore muscle function when transplanted near paralyzed muscles. Together, these experiments will be the first ever to examine whether different motoneuron subtypes can be generated from ES cells and iPS cells and whether their creation and use will lead to better function of paralyzed muscles in patients with ALS or in those suffering from a SCI.