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Modeling Niemann-Pick disease with iPSC-derived NSCs

Review of “Induced Pluripotent Stem Cells for Disease Modeling and Evaluation of Therapeutics for Niemann-Pick Disease Type A” from Stem Cells Translational Medicine by Stuart P. Atkinson

Niemann-Pick disease type A (NPA) is an autosomal recessive disorder [1] caused by mutations in the gene encoding the acid sphingomyelinase (ASM) protein [2]. The mutation allows the accumulation of sphingomyelin (SM), a form of sphingolipid found in cell membranes, in enlarged patient lysosomes [3] and this severely impacts the central nervous system and other organs [4]. These effects are only made worse by the lack of NPA therapies and this situation prompted a new study from Wei Zheng (NIH, Bethesda, Maryland, USA) [5].

Employing NPA patient samples, Long et al generated and differentiated NPA patient-specific induced pluripotent stem cells (iPSCs) into neural stem cells (NPA-NSCs) which exhibited the expected NPA disease phenotype of sphingomyelin accumulation and enlarged lysosomes. 

To ascertain the suitability of NPA-NSCs as a potential disease model, the authors tested three compounds known to reduce lysosomal lipid accumulation in Niemann-Pick disease (d-tocopherol, a-tocopherol, and Hydroxypropyl-b-cyclodextrin [HPBCD]) as well as enzyme (ASM) replacement therapy [6]. Encouragingly, all three compounds reduced sphingomyelin accumulation and lysosomal size in NPA-NSCs and exogenous ASM treatment also reduced sphingomyelin accumulation (See Figure for effect of ASM in two NPA-NSC lines). However, a combination of all three compounds and enzyme replacement therapy created a strong synergistic effect and almost completely ameliorated sphingomyelin accumulation in NPA-NSCs.

A double whammy of a result! Not only are iPSC-derived NSCs a suitable model system, but the authors also have uncovered an effective treatment combination which can reduce the main symptoms associated with Niemann-Pick disease. Nevertheless, the authors hope to work with additional patient samples, to employ NPA-NSCs to model disease progression, and to screen for even more effective drugs or drug combinations.


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  6. Yu D, Swaroop M, Wang M, et al. Niemann-Pick Disease Type C: Induced Pluripotent Stem Cell-Derived Neuronal Cells for Modeling Neural Disease and Evaluating Drug Efficacy. J Biomol Screen 2014;19:1164-1173.