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

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.