%0 Journal Article
%T Intracerebroventricular 2-hydroxypropyl-γ-cyclodextrin alleviates hepatic manifestations without distributing to the liver in a murine model of Niemann-Pick disease type C.
%A Yamada Y
%A Ishitsuka Y
%A Fukaura-Nishizawa M
%A Kawata T
%A Ishii A
%A Shirakawa A
%A Sakai T
%A Tanaka M
%A Kondo Y
%A Takeo T
%A Nakagata N
%A Motoyama K
%A Higashi T
%A Arima H
%A Seki T
%A Kurauchi Y
%A Katsuki H
%A Higaki K
%A Ikeda R
%A Matsuo M
%A Era T
%A Irie T
%J Life Sci
%V 350
%N 0
%D 2024 Aug 1
%M 38852794
%F 6.78
%R 10.1016/j.lfs.2024.122776
%X Niemann-Pick disease type C (NPC) is a lysosomal lipid storage disorder characterized by progressive neurodegeneration and hepatic dysfunction. A cyclic heptasaccharide, 2-hydroxypropyl-β-cyclodextrin (HP-β-CD), is currently under clinical investigation for NPC, but its adverse events remain problematic. We previously identified that a cyclic octasaccharide, 2-hydroxypropyl-γ-cyclodextrin (HP-γ-CD), also ameliorated NPC manifestations with higher biocompatibility than HP-β-CD. However, preclinical studies describing the associations between the biodistribution and pharmacodynamics of these compounds, which are essential for clinical application, are still lacking. Here, we investigated these properties of HP-γ-CD by measuring its organ biodistribution and therapeutic effect after systemic and central administration. The effect of HP-γ-CD on disturbed cholesterol homeostasis appeared within several hours after exposure and persisted for several days in NPC model cells and mice. Tissue distribution indicated that only a small fraction of subcutaneously administered HP-γ-CD rapidly distributed to peripheral organs and contributed to disease amelioration. We found that a subcutaneous dose of HP-γ-CD negligibly ameliorated neurological characteristics because it has limited penetration of the blood-brain barrier; however, an intracerebroventricular microdose unexpectedly attenuated hepatic dysfunction without the detection of HP-γ-CD in the liver. These results demonstrate that central administration of HP-γ-CD can indirectly attenuate peripheral manifestations of NPC.