Disease Pluripotent Stem (iPS) Cells

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DESCRIPTION (provided by applicant): Spinal muscular atrophy (SMA) is a progressive neurodegenerative disease caused by mutations in the "survival of motor neuron (SMN)" gene, leading to spinal motor neuron degeneration and muscular atrophy. It is one of the leading causes of infant death without an effective treatment. This pilot proposal intends to create a cellular model of SMA using SMA patient's skin cells. Specifically, we will first induce pluripotent stem (iPS) cells from an SMA patient's fibroblasts by expressing pluripotent transcription factors using a recently established method. We will then direct the SMA-iPS cells, alongside non-SMA iPS cells and human embryonic stem cells (NIH Registry: WA07 and WA09), toward spinal motor neurons using our reproducible differentiation protocol established for human embryonic stem cells. We will determine if the development (differentiation, neurite extension) and function (axonal transportation, interactions with muscles) of motor neurons derived from the SMA-iPS cells are defective. Thus, we will create for the first time SMA-specific human iPS cells, which will permit studies on the pathogenesis of spinal motor neuron degeneration under the human genetic background. This system can also serve as a simple but bona fide human SMA target for therapeutic screening, our main goal. PUBLIC HEALTH RELEVANCE: We are building stem cells from the skin cells of patients with spinal muscular atrophy (SMA). The stem cells 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 simple but bona fide human SMA target for therapeutic screening, which may ultimately lead to the discovery of a treatment for SMA.