Inclusion Solves Insolubility ―Translational Research Cycle from Bedside to Bench and Bench to Bedside for Drug Development Targeting Niemann-Pick Disease Type C―

Abstract

Cyclodextrins (CDs) are used not only as pharmaceutical excipients but also as active pharmaceutical ingredients. CDs can act as artificial carriers or shuttles to ameliorate lipid transport disorders. Niemann-Pick disease type C (NPC) is an inherited, progressive neurodegenerative disorder caused by mutations in NPC1 or NPC2 genes, in which unesterified cholesterol accumulates in lysosomes and the transport of cholesterol from lysosomes to the endoplasmic reticulum is impaired. 2-Hydroxypropyl-β-CD (HPBCD) has activity as a cholesterol shuttle and can attenuate NPC-related manifestations in model cells and animals. HPBCD can also be an effective treatment for NPC patients, but has produced lung damage and ototoxicity at therapeutic doses in clinical trials. Like HPBCD, 2-hydroxypropyl-γ-CD (HPGCD) can normalize disrupted cholesterol homeostasis in cells derived from NPC patients and NPC model mice. HPGCD interacts with unesterified cholesterol with a mode of interaction distinct from that of HPBCD and acts as a fine-tuned cholesterol shuttle for the treatment of NPC with a wider safety margin than HPBCD in terms of ototoxicity and pulmonary toxicity. By bridging clinical and basic research, it is hoped that progress will be made in the development of therapeutic agents against neurodegenerative lipid storage disorders that share common pathogenic mechanisms with NPC.