Influence of Npc1 genotype on the toxicity of hydroxypropyl-β-cyclodextrin, a potentially therapeutic agent, in Niemann–Pick Type C disease models

Abstract

Hydroxypropyl-β-cyclodextrin (HPBCD) is an attractive drug candidate against Niemann-Pick Type C (NPC) disease. However, the safety of HPBCD treatment for NPC patients remains to be elucidated. In this study, we examined the acute toxicity of HPBCD in <i>Npc1</i>-deficient mice. When treated with HPBCD (20,000 mg/kg, subcutaneously), over half of the wild-type (<i>Npc1</i>^+/+) or <i>Npc1</i>^+/- mice died by 72 h after the injection. In contrast, all of the <i>Npc1</i>^-/- mice survived. Marked pathophysiological changes, such as an elevation in serum transaminase and creatinine levels, hepatocellular necrosis, renal tubular damage, interstitial thickening, and hemorrhages in lungs, were induced by the HPBCD treatment in <i>Npc1</i>^+/+ or <i>Npc1</i>^+/- mice. However, these pathophysiological changes were significantly alleviated in <i>Npc1</i>^-/- mice. In addition, <i>in vitro</i> analysis showed that the <i>Npc1</i> gene deficiency and treatment with U18666A, an Npc1 inhibitor, remarkably attenuated the cytotoxicity of HPBCD in Chinese hamster ovary cells. These results suggest that the <i>NPC1</i> genotype exacerbates the cytotoxicity of HPBCD and <i>Npc1</i>^-/- mice have substantial resistance to the lethality and the organ injury induced by HPBCD injection compared with <i>Npc1</i>^+/+ or <i>Npc1</i>^+/- mice. We suggest that the <i>Npc1</i> genotype should be considered in the safety evaluation of HPBCD using experimental animals and cells.