Availability of large quantities of functional neurons that are genetically identical to a patient has exciting potential in modeling cellular neurodegenerative processes and for drug screening. Induced pluripotent stem cell technology offered the first example to generate disease-specific neurons, which is nevertheless laborious and inefficient. We propose to directly convert spinal muscular atrophy (SMA) patients'fibroblasts to spinal motor neurons (MNs) using a novel lineage reprogramming technology -- induced neural (iN) cell technology developed by Wernig and colleagues. We will first develop a platform for converting mouse fibroblasts to functionally specialized spinal MNs based on our identification of the set of core transcription factors (TFs) for MN specification and using an inducible lentiviral system. We will then apply this approach, with or without modifications, to induce MNs from fibroblasts that are derived from SMA patients. We will further examine whether the SMA MNs retain the genetic background and exhibit the disease-related phenotypes. This exploratory application, if successful, will open a new avenue for understanding the pathological processes of SMA and for developing treatment options for the devastating disease.
We are reprogramming motor neurons from the skin fibroblasts of patients with spinal muscular atrophy (SMA). The induced SMA motor neurons will offer a model system to study the pathogenesis of spinal motor neuron degeneration under the human genetic background. It can also serve as a high-through platform for drug screening, which may ultimately lead to the discovery of new treatment for SMA.