Title
Therapeutic agent for Niemann-Pick disease type C
Background and Purpose of Research
Niemann-Pick disease type C (NPC) is characterized by accumulation of cholesterol in cells caused bycholesterol transport disorder in cells. Treated NPC patients currently receive miglustat which yields
extension of survival period of patients, but which provides no further therapeutic effect. It is also
known that administration of cyclodextrin to NPC disease cellular model reduces accumulation ofcholesterol. However, whilst cholesterol is removed by cyclodextrin, there is no act by cyclodextrin on
alleviation of cholesterol transport disorder, therefore cyclodextrin will not lead to drastic treatment ofNPC. Inasmuch as NPC is an intractable disease, and when contracted by infants, produces motor
functional disorder and neurological disorder, and can cause death at their ages of around 10, there isurgent need for a novel drastic therapy. The purpose of this research is to remedy cholesterol transport
disorder and provide a novel therapeutic agent, thus conducive to drastic therapy, for NPC.
Summary of Research Results
For NPC disease cellular model, researchers used NPC1 gene deficient cell (CHO-NPC) derived from
Chinese hamster ovary (CHO) cells. Researchers demonstrated the effect of ceramide 1-phosphate (C1P)
inhibitor on the accumulation of cholesterol in NPC disease cellular model. Based on that, researchers
strive to develop a novel therapeutic agent for NPC, the action mechanism of which consists of remedyof cholesterol transport disorder by suppression of ceramide kinase.

Figure 1: Applying a cell culture medium containing LPDS (lipoprotein-deficient serum) in culturing wildtype cell and NPC disease cell, there ensue depletion of cholesterol in the endoplasmic reticulum, andtransition of SREBP1(lipid synthesis transcription factor) into nucleus of the cell (nucleus is coloredyellow). Consequence of imposition thereonto of LDL (low-density lipoprotein) in the case of wild-type
cell is such that SREBP1 disappear from nucleus (nucleus is colored red) because there occur cholesteroltransport to the endoplasmic reticulum, whereas consequence in the case of NPC disease cell is such thatdisappear of SREBP1 is limited and restricted because cholesterol stays in the late endosome. This
limitation and restriction is resolved by administration of ceramide kinase inhibitor (NVP-231) which
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suppresses production of C1P. The implication is that suppression of ceramide kinase provides remedy tocholesterol transport disorder in NPC disease cell.

Figure 2: CHO-NPC indicates accumulation of cholesterol. However, administration of ceramide kinase
inhibitor (NVP-231) thereon has the effect of reducing the accumulation of cholesterol. Additionally,
whereas administration of control siRNA (siControl) on patient’s skin fibroblasts indicates accumulationof cholesterol, administration of ceramide kinase selective siRNA (siCerK) or administration of NVP-231
on the same fibroblasts indicates reduction of accumulation of cholesterol.
Advantages
Capable of remedying cholesterol transport disorder and providing a novel, conducive to drastic
treatment, for NPC, in contrast to existing technology which lacks such capability.
Applications
Therapy of NPC.
Inventors
Hiroyuki Nakamura, Toshihiko Murayama
Licensing Contact
Future Medicine Education and Research Organization at Chiba University
E-mail: mirai-shien@chiba-u.jp

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