Niemann–Pick disease type C (NPC) is a recessive hereditary disease caused by mutation of the NPC1 or NPC2 gene. It is characterized by abnormality of cellular cholesterol trafficking with severe neuronal and hepatic injury. In this study, the potential of glycoprotein nonmetastatic melanoma protein B (GPNMB) as a biomarker reflecting the therapeutic effect of 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) in an NPC mouse model was investigated. Serum, brain, and liver expression levels of GPNMB were measured, and their therapeutic effects on NPC manifestations in the brain and liver were evaluated. Intracerebroventricular HP-β-CD inhibited cerebellar Purkinje cell damage in Npc1−/− mice and significantly reduced serum and cerebellar GPNMB levels. Interestingly, it was also observed that the intracerebral administration significantly reduced hepatic GPNMB expression and elevated serum ALT in Npc1−/− mice. Repeated doses of intracerebroventricular HP-β-CD (30 mg/kg, started at 4 weeks of age and repeated every 2 weeks) drastically extended the lifespan of Npc1−/− mice compared with saline treatment. In summary, the results suggest that GPNMB level in serum is a potential biomarker for evaluating the attenuation of NPC pathophysiology by intracerebroventricular HP-β-CD treatment.
Fukaura, M.; Ishitsuka, Y.; Shirakawa, S.; Ushihama, N.; Yamada, Y.; Kondo, Y.; Takeo, T.; Nakagata, N.; Motoyama, K.; Higashi, T.; Arima, H.; Kurauchi, Y.; Seki, T.; Katsuki, H.; Higaki, K.; Matsuo, M.; Irie, T. Intracerebroventricular Treatment with 2-Hydroxypropyl-β-Cyclodextrin Decreased Cerebellar and Hepatic Glycoprotein Nonmetastatic Melanoma Protein B (GPNMB) Expression in Niemann–Pick Disease Type C Model Mice. Int. J. Mol. Sci. 2021, 22, 452. https://doi.org/10.3390/ijms22010452