Study investigates what goes wrong in familial dysautonomia and assesses potential treatments
Induced pluripotent stem (iPS) cells promise to give researchers new ways to study diseases, but even though several groups have now generated iPS cells from patient samples representing a variety of maladies, they have not yet demonstrated that the cells differentiate or behave differently from their nondiseased counterparts. New work now shows clear phenotypic differences in iPS cells generated from patients with a rare, fatal neuropathy called familial dysautonomia1. It's a demonstration that iPS cells can expand researchers' toolkits, explains Lorenz Studer, who led the work. “In a carefully selected genetic disease, iPS cell technology can provide actual insights into disease process and the validation of candidate drugs.”
Familial dysautonomia is caused by a point mutation in the IKBKAP gene. The rare disease is particularly difficult to study because researchers lack animal models and access to affected human tissues. Studer and colleagues at the Sloan-Kettering Institute in New York generated iPS cell lines from patients with and without the disease and put the cells through protocols to differentiate them into neural crest cells and peripheral neurons. Those carrying the mutation were different from those without it in several ways: they had lower expression of several genes involved in making peripheral neurons; they made very low levels of the IkB kinase complex protein coded for by the IKBKAP gene; they generated fewer neurons; and the neural crest precursor cells generated were less mobile.
Previous research on blood cells from diseased patients had already identified comparatively low levels of the functional IKBKAP transcript as well as a handful of compounds that affected these levels. Studer and colleagues decided to assess the compounds' effects on their iPS cell–derived neural cells: only one compound, a plant hormone called kinetin, increased the level of normal transcripts. Short-term doses of the compound raised levels of the transcript but did not affect the other defects. Long-term exposure, beginning before the iPS cells were differentiated, did increase the rates at which cells differentiated toward neurons but did not, disappointingly, improve mobility.
The gene-expression patterns will be particularly valuable for finding new targets for familial dysautonomia therapies and finding markers to evaluate the targets, says Berish Rubin, head of the Laboratory for Familial Dysautonomia Research at Fordham University in New York. He cautions that a new tool is a long way from a new therapy. “While cell lines allow for the identification of compounds with therapeutic potential, it is the in vivo impact of these compounds that will make a difference in the lives of those with familial dysautonomia.” Nonetheless, he says, “The tools [Studer and colleagues] have developed clearly add to those that are currently available”.
Lee, G. et al. Modelling pathogenesis and treatment of familial dysautonomia using patient-specific iPSCs. Nature advance online publication, 10.1038/nature08320 (19 August 2009).
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Baker, M. iPS cells used to probe rare neurodegenerative disease. Nat Rep Stem Cells (2009). https://doi.org/10.1038/stemcells.2009.114