UNIVERSITY OF WISCONSIN SYSTEM
Spinal muscular atrophy (SMA) is the leading genetic cause of infantile death and occurs in 1:6,000 to 1:10,000 live births. SMA is caused by a homozygous loss of the survival motor neuron-1 (SMN) gene leading to the progressive loss of alpha-motor neurons in the spinal cord causing atrophy of trunk and limb muscles. The therapeutic use of stem cells for the treatment of neurological disorders depends on the ability to generate specific cell types. Although humans have a second copy of SMN (SMN2), this gene contains a non-polymorphic C to T transition that produces an unstable, truncated protein lacking the function of the full-length protein produced by the SMN1 gene. Current experimental models used for the study of SMA rely on human cell lines or SMA patient fibroblasts, neither of which make the motor neuron population particularly affected, or rodent motor neurons derived from transgenic mice carrying the SMN1 mutation. However, mice do not have SMN2 so the disease process or mechanisms might not be as relevant to the human disease. Human embryonic stem cells can be instructed to generate the specific cell types of interest, but ethical objections to their use as well as necessary genetic manipulations to generate the SMN1 mutation limit their usefulness. With the advent of new stem cell technologies, the generation of induced pluripotent stem (iPS) cells from adult skin has opened new avenues of studying neurodegenerative diseases because of the potential to generate a patient-specific iPS cell line. We have generated iPS cells from a child with SMA and his non-affected mother, and in this exploratory research proposal, we aim to develop neurons (specifically motor neurons), astrocytes, and muscle cells from these cells. The generation of patient and/or disease-specific iPS cells will be a platform upon which a wide range of experiments can be performed, including understanding disease mechanisms, neuronal vulnerability, and therapeutic drug screening, all of which are relevant to the NIH mission to improve public health.