In Vitro and In Vivo Evaluation of 6-O-?-Maltosyl-?-Cyclodextrin as a Potential Therapeutic Agent Against Niemann-Pick Disease Type C.

ABSTRACT: Niemann-Pick disease Type C (NPC) is a rare lysosomal storage disease characterized by the dysfunction of intracellular cholesterol trafficking with progressive neurodegeneration and hepatomegaly. We evaluated the potential of 6-O-?-maltosyl-?-cyclodextrin (G2-?-CD) as a drug candidate against NPC. The physicochemical properties of G2-?-CD as an injectable agent were assessed, and molecular interactions between G2-?-CD and free cholesterol were studied by solubility analysis and two-dimensional proton nuclear magnetic resonance spectroscopy. The efficacy of G2-?-CD against NPC was evaluated using Npc1 deficient Chinese hamster ovary (CHO) cells and Npc1 deficient mice. G2-?-CD in aqueous solution showed relatively low viscosity and surface activity; characteristics suitable for developing injectable formulations. G2-?-CD formed higher-order inclusion complexes with free cholesterol. G2-?-CD attenuated dysfunction of intercellular cholesterol trafficking and lysosome volume in Npc1 deficient CHO cells in a concentration dependent manner. Weekly subcutaneous injections of G2-?-CD (2.9 mmol/kg) ameliorated abnormal cholesterol metabolism, hepatocytomegaly, and elevated serum transaminases in Npc1 deficient mice. In addition, a single cerebroventricular injection of G2-?-CD (21.4 ?mol/kg) prevented Purkinje cell loss in the cerebellum, body weight loss, and motor dysfunction in Npc1 deficient mice. In summary, G2-?-CD possesses characteristics favorable for injectable formulations and has therapeutic potential against in vitro and in vivo NPC models.

SUBMITTER: Yasmin N 

PROVIDER: S-EPMC6429330 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature