RESEARCH Open Access Neural stem cells for disease modeling of Wolman disease and evaluation of therapeutics Francis Aguisanda 1,3† , Charles D. Yeh 1† , Catherine Z. Chen 1 , Rong Li 1 , Jeanette Beers 2 , Jizhong Zou 2 , Natasha Thorne 1,4* and Wei Zheng 1* Abstract Background: Wolman disease (WD) is a rare lysosomal storage disorder that is caused by mutations in the LIPA gene encoding lysosomal acid lipase (LAL). Deficiency in LAL function causes accumulation of cholesteryl esters and triglycerides in lysosomes. Fatality usually occurs within the first year of life. While an enzyme replacement therapy has recently become available, there is currently no small-molecule drug treatment for WD. Results: We have generated induced pluripotent stem cells (iPSCs) from two WD patient dermal fibroblast lines and subsequently differentiated them into neural stem cells (NSCs). The WD NSCs exhibited the hallmark disease phenotypes of neutral lipid accumulation, severely deficient LAL activity, and increased LysoTracker dye staining. Enzyme replacement treatment dramatically reduced the WD phenotype in these cells. In addition, δ-tocopherol (DT) and hydroxypropyl-beta-cyclodextrin (HPBCD) significantly reduced lysosomal size in WD NSCs, and an enhanced effect was observed in DT/HPBCD combination therapy. Conclusion: The results demonstrate that these WD NSCs are valid cell-based disease models with characteristic disease phenotypes that can be used to evaluate drug efficacy and screen compounds. DT and HPBCD both reduce LysoTracker dye staining in WD cells. The cells may be used to further dissect the pathology of WD, evaluate compound efficacy, and serve as a platform for high-throughput drug screening to identify new compounds for therapeutic development. Keywords: Wolman disease, Lysosomal storage disease, Induced pluripotent stem cells, Neural stem cells, Cell-based disease model Background Wolman disease is a rare lysosomal storage disorder with an incidence rate of less than 1 in 100,000 births [1]. WD is caused by mutations in the gene encoding lysosomal acid lipase (LAL), which results in nonfunc- tional levels of LAL activity. This leads to the accumula- tion of triglycerides (TG) and cholesteryl esters (CE) in the lysosomes of many cells and tissues [2]. Clinical manifestations include adrenal calcification, hepatosple- nomegaly, and enlarged lymph nodes [3]. These organ and tissue enlargements are due to the accumulation of TG and CE, which may also occur in the intestine and central nervous system [4–6]. Typical life expectancy of patients without treatment is less than one year of age, with death due to multi-organ failure. Complications of WD are thought to be related to malabsorption. Parenteral hyperalimentation has been shown to slow patient deterioration but not cure the dis- ease [7]. Hematopoietic stem cell transplantation has been moderately successful for treating WD, but the procedure remains risky [8, 9]. Enzyme replacement therapy (ERT)—with sebelipase alfa (KANUMA®)—has recently been approved for treating WD [10, 11]. While ERT has reduced abdominal distention, hepatospleno- megaly, vomiting and diarrhea, and improved survival * Correspondence: Natasha.Thorne@fda.hhs.gov; wzheng@mail.nih.gov † Equal contributors 1 National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, USA Full list of author information is available at the end of the article © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Aguisanda et al. Orphanet Journal of Rare Diseases (2017) 12:120 DOI 10.1186/s13023-017-0670-9