DepartmentCell Modulation
Publication date27-Apr-2015

Soga, M., Ishitsuka, Y., Hamasaki, M., Yoneda, K., Furuya, H., Matsuo, M., Ihn, H., Fusaki, N., Nakamura, K., Nakagata, N., Endo, F., Irie, T., Era, T. HPGCD outperforms HPBCD as a potential treatment for Niemann-Pick disease type C during disease modeling with iPS cells. Stem Cells33(4):1075-1088 (2015)

Niemann-Pick disease type C (NPC) is a lysosomal storage disease characterized by abnormal accumulation of free cholesterol and glycolipids. Here, we established induced pluripotent stem cell (iPSC) lines from NPC patients. Hepatocyte-like cells (HLCs) and neural progenitors derived from the iPSC lines accumulated cholesterol and displayed impaired autophagy and ATP production. A molecular signature related to lipid metabolism was also impaired in the NPC-iPSC-derived HLCs. These findings indicate that iPSC-derived cells can phenocopy human NPC. We also newly found that 2-hydroxypropyl-γ-cyclodextrin (HPGCD) could reduce the cholesterol accumulation and restore the functional and molecular abnormalities in the NPC patient-derived cells (Figure), and do so more effectively than 2-hydroxypropyl-β-cyclodextrin treatment. In addition, NPC model mice showed an improved liver status and prolonged survival with HPGCDs. Thus, iPSC lines derived from patient cells are powerful tools to study cellular models of NPC, and HPGCD is a potential new drug candidate for future treatment of this disease.



Figure: Effects of HPGCD on cholesterol accumulation and restoration of cellular functions in NPC-derived HLCs.
A) HPGCD and HPBCD, but not HPACD and Miglustat treatment, significantly reduced free cholesterol accumulation in the NPC-derived HLCs. Upper left panel: Immunostaining of Albumin (green) and PI (propidium iodide) (red), Lower left panel: Filipin staining which specifically detects free cholesterol, Right graph: Analysis of filipin staining with IN Cell Analyzer

B) HPGCD and HPBCD, but not Miglustat treatments restored ATP levels and the abnormal induction of autophagy in NPC-derived HLCs. Left graph: ATP production, Right panel: Autophagy, N1-12: Healthy donor-derived HLCs, NPC6-1 NPC-derived HLCs