In vivo Efficacy and Safety Evaluation of Lactosyl-β-cyclodextrin as a Therapeutic Agent for Hepatomegaly in Niemann-Pick Type C Disease

Niemann-Pick type C disease (NPC) is a fatal, autosomal recessive disorder, which causes excessive accumulation of free cholesterol in endolysosomes, resulting in progressive hepatomegaly and neurodegeneration. Currently, 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CyD) is used at a high dose for the treatment of NPC, risking lung toxicity and hearing loss during treatment. One method to reduce the required dose of HP-beta-CyD for the treatment of hepatomegaly is to actively deliver beta-cyclodextrin (beta-CyD) to hepatocytes. Previously, we synthesized lactosyl-beta-CyD (Lac-beta-CyD) and demonstrated that it lowers cholesterol in NPC model liver cells. In the present study, we studied the efficacy and safety of Lac-beta-CyD treatment of hepatomegaly in Npc1(-/-) mice. After subcutaneous administration, Lac-beta-CyD accumulated in the liver and reduced hepatomegaly with greater efficacy than HP-beta-CyD. In addition, subcutaneous administration of a very high dose of Lac-beta-CyD was less toxic to the lungs than HP-beta-CyD. Notably, the accumulation of intracellular free cholesterol in endolysosomes of NPC-like liver cells was significantly lower after administration of Lac-beta-CyD than after treatment with HP-beta-CyD. In conclusion, these results suggest that Lac-beta-CyD is a candidate for the effective treatment of hepatomegaly in NPC.