HPGCD Outperforms HPBCD as a Potential Treatment for Niemann-Pick Disease Type C During Disease Modeling with iPS Cells

Abstract

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-iPSCderived HLCs. These findings indicate that iPSC-derived cells can phenocopy human NPC. We also newly found that 2-hydroxypropyl-c-cyclodextrin (HPGCD) could reduce the cholesterol accumulation and restore the functional and molecular abnormalities in the NPC patientderived cells, and do so more effectively than 2-hydroxypropyl-b-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.

Intrathecal 2-hydroxypropyl-beta-cyclodextrin in a single patient with Niemann–Pick C1

“…In a recent publication, 2-hydroxypropyl-gamma-cyclodextrin was found to more efficiently reduce the cholesterol accumulation and restore the functional abnormalities in induced pluripotent stem cell lines from NPC1 patients [29]. Preclinical studies have not yet been reported on this compound.…”

Supramolecular Pharmaceutical Sciences: A Novel Concept Combining Pharmaceutical Sciences and Supramolecular Chemistry with a Focus on Cyclodextrin-Based Supermolecules

“…Recently, various bioactivities of CyDs have been demonstrated, and CyDs have been used as active pharmaceutical ingredients (APIs) against Niemann-Pick disease type C (NPC), [62][63][64][65][66][67][68][69][70][71][72][73][74][75][76] leukemia, 77) hyperlipidemia, 78) Alzheimer's disease, [79][80][81][82][83][84] cerebral ischemic injury, 85) atherosclerosis, 86) diabetic kidney disease, 87) chronic renal failure, 88) AIDS, 89,90) influenza, 91) peripheral artery disease, 92) sterility, [93][94][95] solid cancers, [96][97][98][99][100][101] bacterial growth, 102) α-synucleinopathy, 103) GM1-gangliosidosis, 104) septic shock, [105][106][107] hypervitaminosis, 108) and transthyretin-related familial amyloidotic polyneuropathy (FAP) …”

Potential Use of Cyclodextrins as Drug Carriers and Active Pharmaceutical Ingredients

“…Based on the results regarding cholesterol solubilizing potential, attenuating the effects against NPC abnormalities and cytotoxicity induction, HB-β-CyD may be superior in terms of safety and efficacy in Npc1 null cells compared with HE-β-CyD and HB-β-CyD. On the other hand, Soga et al 56) reported that 2-hydroxypropyl-γ-CyD (HP-γ-CyD) could reduce cholesterol accumulation and restore functional and molecular abnormalities in NPC patient-derived cells, more effectively than HP-β-CyD treatment. In addition, NPC model mice showed improved liver status and prolonged survival with HP-γ-CyD.…”