POTENTIAL USE OF CYCLODEXTRIN DERIVATIVES AS THERAPEUTIC AGENTS FOR LYSOSOMAL STORAGE DISORDERS
Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan
Lysosomal storage disorders (LSDs) are a class of more than 50 rare inherited disorders, and are characterized by the accumulation of undegraded lipids and saccharides in lysosomes. Niemann-Pick disease type C (NPC) is an autosomal recessive lysosomal storage disorder, which is an inherited disease characterized by the accumulation of unesterified cholesterol in endolysosomes. Recently, 2-hydroxypropyl-β-cyclodextrin (HP-β-CyD) has been used for the treatment of NPC, and ameliorated a hepatosplenomegaly in the patients. In addition, 2-hydroxypropyl-γ-cyclodextrin (HP-γ-CyD) could reduce the cholesterol accumulation and restore the functional and molecular abnormalities in the NPC patient-derived cells, and do so more effectively than HP-β-CyD treatment. However, to obtain the treatment efficacy, high doses of HP-β-CyD and HP-γ-CyD were necessary. Therefore, the decrease in doses by using active intracellular delivery system of β-CyD to NPC cells is expected. In this study, to efficiently deliver β-CyD to NPC cells, we newly synthesized octaarginine (R8)-appended β-CyD (R8-β-CyD) and lactose-appended β-CD (Lac-β-CyD). As a result, R8-β-CyD and Lac-β-CyD significantly decreased intracellular cholesterol content, compared with HP-β-CyD, suggest that R8-β-CyD and Lac-β-CyD may be promising therapeutic agents for ameliorating cholesterol accumulation in NPC. In addition, GM1-gangliosidosis is an inherited disorder characterized by the accumulation of GM1-gangliosides in many tissues and organs, particularly in the brain. Currently, there is no treatment available for patients with ganglioside storage diseases. The treatment with methyl-β-CyD and dimethyl-α-CyD (DM-α-CyD) decreased GM1-ganglioside levels. Taken together, these results suggest that CyDs may have the potential as drugs for NPC and GM1-gangliosidosis.
Keywords: Lysosomal, therapeutic, treatment, delivery.