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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21NS064578-02
Application #
7826977
Study Section
Neurogenesis and Cell Fate Study Section (NCF)
Program Officer
Porter, John D
Project Start
2009-05-15
Project End
2012-06-30
Budget Start
2010-07-01
Budget End
2012-06-30
Support Year
2
Fiscal Year
2010
Total Cost
$222,750
Indirect Cost
Name
University of Wisconsin Madison
Department
Pediatrics
Type
Other Domestic Higher Education
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Du, Zhong-Wei; Chen, Hong; Liu, Huisheng et al. (2015) Generation and expansion of highly pure motor neuron progenitors from human pluripotent stem cells. Nat Commun 6:6626
Liu, Huisheng; Lu, Jianfeng; Chen, Hong et al. (2015) Spinal muscular atrophy patient-derived motor neurons exhibit hyperexcitability. Sci Rep 5:12189
Lu, Jianfeng; Liu, Huisheng; Huang, Cindy Tzu-Ling et al. (2013) Generation of integration-free and region-specific neural progenitors from primate fibroblasts. Cell Rep 3:1580-91
Xi, Jiajie; Liu, Yan; Liu, Huisheng et al. (2012) Specification of midbrain dopamine neurons from primate pluripotent stem cells. Stem Cells 30:1655-63
Ma, Lixiang; Hu, Baoyang; Liu, Yan et al. (2012) Human embryonic stem cell-derived GABA neurons correct locomotion deficits in quinolinic acid-lesioned mice. Cell Stem Cell 10:455-64
Liu, Huisheng; Zhang, Su-Chun (2011) Specification of neuronal and glial subtypes from human pluripotent stem cells. Cell Mol Life Sci 68:3995-4008
Krencik, Robert; Zhang, Su-Chun (2011) Directed differentiation of functional astroglial subtypes from human pluripotent stem cells. Nat Protoc 6:1710-7
Krencik, Robert; Weick, Jason P; Liu, Yan et al. (2011) Specification of transplantable astroglial subtypes from human pluripotent stem cells. Nat Biotechnol 29:528-34
Liu, Yan; Zhang, Su-Chun (2010) Human stem cells as a model of motoneuron development and diseases. Ann N Y Acad Sci 1198:192-200
Zhang, Xiao-Qing; Zhang, Su-Chun (2010) Differentiation of neural precursors and dopaminergic neurons from human embryonic stem cells. Methods Mol Biol 584:355-66

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