Modeling Pathogenesis and Treatment of Familial Dysautonomia using Patient Specific iPSCs

By Gabsang Lee, E. Papapetrou, Hyesoo Kim, S. M. Chambers, M. Tomishima, Christopher A. Fasano, Yosif M. Ganat, J. Menon, F. Shimizu, A. Viale and 3 more. Nature, 2009

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The isolation of human induced pluripotent stem cells (iPSCs) offers a new strategy for modelling human disease. Recent studies have reported the derivation and differentiation of disease-specific human iPSCs. However, a key challenge in the field is the demonstration of disease-related phenotypes and the ability to model pathogenesis and treatment of disease in iPSCs. Familial dysautonomia (FD) is a rare but fatal peripheral neuropathy, caused by a point mutation in the IKBKAP gene involved in transcriptional elongation. The disease is characterized by the depletion of autonomic and sensory neurons. The specificity to the peripheral nervous system and the mechanism of neuron loss in FD are poorly understood owing to the lack of an appropriate model system. Here we report the derivation of patient-specific FD-iPSCs and the directed differentiation into cells of all three germ layers including peripheral neurons. Gene expression analysis in purified FD-iPSC-derived lineages demonstrates tissue-specific mis-splicing of IKBKAP in vitro. Patient-specific neural crest precursors express particularly low levels of normal IKBKAP transcript, suggesting a mechanism for disease specificity. FD pathogenesis is further characterized by transcriptome analysis and cell-based assays revealing marked defects in neurogenic differentiation and migration behaviour. Furthermore, we use FD-iPSCs for validating the potency of candidate drugs in reversing aberrant splicing and ameliorating neuronal differentiation and migration. Our study illustrates the promise of iPSC technology for gaining new insights into human disease pathogenesis and treatment.

Subfields: Cell Biology, Cellular and Molecular Neuroscience

View Paper: https://www.semanticscholar.org/paper/9bb6924c1b78d4758dc348a89a5ef591c19411ed

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Citations in the corpus

Generation of isogenic pluripotent stem cells differing exclusively at two early onset Parkinson point mutations (2011, neutral): “However, so far, only a few such studies have identified disease-related phenotypes, mostly in rare, early age onset or metabolic diseases (Brennand et al., 2011; Ebert et al., 2009; Itzhaki et al., 2011; Lee et al., 2009; Marchetto et al., 2010; Rashid et al., 2010).”
A model for neural development and treatment of Rett Syndrome using human induced pluripotent stem cells (2010, background): “Although iPSCs have been generated for several neurological diseases (Dimos et al., 2008; Ebert et al., 2009; Hotta et al., 2009; Lee et al., 2009; Park et al., 2008; Soldner et al., 2009), the demonstration Cell 143, 527–539, November 12, 2010 ª2010 Elsevier Inc. 527 of disease-specific…”
Induced pluripotency: history, mechanisms, and applications. (2010, background): “2009), familial dysautonomia (FD) (Lee et al. 2009), and LEOPARD syndrome (CarvajalVergara et al.”
Neural differentiation of human induced pluripotent stem cells follows developmental principles but with variable potency (2010, background): “These human iPSCs would overcome the drawbacks of using hESCs and allow for the direct examination of diseased cells for pathological studies and drug screening; this has recently been performed on iPSCs from patients of amyotrophic lateral sclerosis (13), spinal muscular atrophy (14), and familial ”
Cell type of origin influences the molecular and functional properties of mouse induced pluripotent stem cells (2010, background): “Thus, resolving the question of whether iPSCs produced from different cell types are molecularly and functionally equivalent is crucial for using these cells to model disease, which entails detecting subtle differences in the differentiation potential of patient-derived iPSC”
The promise of induced pluripotent stem cells in research and therapy (2012, background): “In 2009, Lee and colleagues harnessed iPS cells to demonstrate disease modelling and drug screening for familial dysautonomia, a rare genetic disorder of the peripheral nervous syste”