Intracerebroventricular 2-hydroxypropyl-β-cyclodextrin improves not only neurological symptoms but also hepatic abnormalities in Niemann-Pick disease type C model mice and patients

[Speaker] Madoka Fukaura:1
[Co-author] Yoichi Ishituka:1, Yuki Kondo:1, Naoki Ushihama:1, Toru Takeo:2, Naomi Nakagata:2, Takumi Era:3, Taishi Higashi:4, Keiichi Motoyama:4, Hidetoshi Arima:4, Yuki Kurauchi:5, Hiroshi Katsuki:5, Shunsuke Kamei:6, Tsuyoshi Shuto:6, Hirofumi Kai:6, Katsumi Higaki:7, Yoshio Sakiyama:8, Takafumi Sakakibara:9, Muneaki Matsuo:10, Tetsumi Irie:1
1:Departmant of Clinical and Chemistry Infomatics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Japan, 2:Division of Reproductive Engineering, Center for Animal Resources and Development (CARD), Kumamoto University, Japan, 3:Department of Cell Modulation, Institute of Molecular Embryology and Genetics, Kumamoto University, Japan, 4:Department of Physical Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Japan, 5:Department of Chemico-Pharmacological Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, Japan, 6:Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, Japan, 7:Research Center for Bioscience and Technology, Tottori University, Japan, 8:Saitama Medical Center, Jichi Medical University, Japan, 9:Department of Pediatrics, Nara Medical University, Japan, 10:Department of Pediatrics, Faculty of Medicine, Saga University, Japan

 Niemann-Pick disease type C (NPC) is a fatal lysosomal lipid storage disorder. NPC patients show severe hepatosplenomegaly and progressive neurodegeneration, therefore the effective cure is needed. 2-Hydroxypropyl-β-cyclodextrin (HPBCD), a cellular cholesterol modifier, has been compassionately used to treat NPC patients by systemic or intracerebroventricular (icv) /intrathecal administration, but the optimal dosage regimen is not yet established. This study was conducted to investigate the effects of systemic or icv HPBCD treatment in Npc1 deficient (Npc1-/-) mice. In addition, we analyzed the clinical data from NPC patients to solve the clinical issues related to the icv-HPBCD therapy.
 To compare the effects of systemic and icv treatment, HPBCD was administered intracerebroventricularly (30 mg/kg, once at 8 weeks of age) or subcutaneously (4000 mg/kg, once a week from 8 weeks of age) in post-symptomatic Npc1-/- mice. In addition, the effects of icv-HPBCD on the pre-symptomatic mice (once at 4 weeks of age) and the post-symptomatic mice were compared. The effects of HPBCD were evaluated by lifespan, body weight, motor function, serum biochemical parameters, and histological assessment. Additionally, we analyzed retrospectively the changes in hepatic functions based on the medical records from NPC patients during the icv-HPBCD treatment.
 The icv-HPBCD significantly prolonged the lifespan and improved motor function even in post-symptomatic Npc1-/-, while the multiple systemic administrations did not show any effects. The beneficial effects of icv-HPBCD were more potent in the pre-symptomatic mice compared with the post-symptomatic mice. Interestingly, the icv-HPBCD significantly attenuated abnormalities in serum transaminase levels, hepatic cholesterol contents and DNA fragmentation in Npc1-/- mice. Microarray analysis in hepatic gene expression also indicated that the changes in hepatic gene expression pattern were normalized by the icv-HPBCD treatment. These data were further supported by the retrospective analyses of the clinical data in which the icv-HPBCD not only ameliorated the neurologic symptoms but also tended to improve the hepatic biochemical parameters and reduce the liver size in NPC patients.
 We suggest that icv-HPBCD, particularly in prophylactic uses, improves not only neuronal symptoms but also hepatic abnormalities in Npc1-/- mice, the results of which were supported by the clinical evidences of the NPC patients.

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