Niemann-Pick disease type C (NPC) is a lysosomal storage disorder with disrupted intracellular cholesterol trafficking. HP-β-CD is a cholesterol solubilizer that is being developed to treat NPC, but its ototoxicity and pulmonary toxicity remain important issues. In this work HP-γ-CD was characterized as a candidate drug to treat NPC.
The mode of interaction between HP-γ-CD and cholesterol was studied by phase-solubility analysis, proton nuclear magnetic resonance spectroscopy, and molecular dynamics simulations. Then the therapeutic superiority of HP-γ-CD was evaluated compared with HP-β-CD using cellular and murine NPC models. Mouse auditory and pulmonary function tests were also conducted.
HP-γ-CD solely formed a 1:1 inclusion complex with cholesterol with an affinity similar to that of HP-β-CD. Consistently, in vitro HP-γ-CD and HP-β-CD amelioration of NPC-related manifestations was almost equivalent at lower concentrations. However, at higher concentrations, the cholesterol inclusion mode of HP-β-CD shifted to the highly-soluble 2:1 complex while that of HP-γ-CD maintained solely the 1:1 complex. The constantly lower cholesterol solubilizing ability of HP-γ-CD conferred it with significantly reduced toxicity compared with HP-β-CD, despite no difference in efficacy in treating NPC model mice.
HP-γ-CD can serve as a fine-tuned cholesterol solubilizer for the treatment of NPC with a wider safety margin than HP-β-CD in terms of ototoxicity and pulmonary toxicity.
Yamada Y, Ishitsuka Y, Kondo Y, Nakahara S, Nishiyama A, Takeo T, Nakagata N, Motoyama K, Higashi T, Arima H, Kamei S, Shuto T, Kai H, Hayashino Y, Sugita M, Kikuchi T, Hirata F, Miwa T, Takeda H, Orita Y, Seki T, Ohta T, Kurauchi Y, Katsuki H, Matsuo M, Higaki K, Ohno K, Matsumoto S, Era T, Irie T. Differential mode of cholesterol inclusion with 2-hydroxypropyl-cyclodextrins impacts safety margin in treating Niemann-Pick disease type C. Br J Pharmacol. 2021 Mar 29. doi: 10.1111/bph.15464. Epub ahead of print. PMID: 33782944.