Niemann-Pick type C (NPC) 1 disease is a rare, inherited, neurodegenerative disease. Clear evidence of the therapeutic efficacy of 2-hydroxypropyl-β-cyclodextrin (HPβCD) in animal models resulted in the initiation of a phase I/IIa clinical trial in 2013 and a phase IIb/III trial in 2015. With clinical trials ongoing, validation of a biomarker to track disease progression and serve as a supporting outcome measure of therapeutic efficacy has become compulsory. In this study, we evaluated calcium-binding protein calbindin D-28K (calbindin) concentrations in the cerebrospinal fluid (CSF) as a biomarker of NPC1 disease. In the naturally occurring feline model, CSF calbindin was significantly elevated at 3 weeks of age, prior to the onset of cerebellar dysfunction, and steadily increased to >10-fold over normal at end-stage disease. Biweekly intrathecal administration of HPβCD initiated prior to the onset of neurologic dysfunction completely normalized CSF calbindin in NPC1 cats at all time points analyzed when followed up to 78 weeks of age. Initiation of HPβCD after the onset of clinical signs (16 weeks of age) resulted in a delayed reduction of calbindin levels in the CSF. Evaluation of CSF from patients with NPC1 revealed that calbindin concentrations were significantly elevated compared with CSF samples collected from unaffected patients. Off-label treatment of patients with NPC1 with miglustat, an inhibitor of glycosphingolipid biosynthesis, significantly decreased CSF calbindin compared with pretreatment concentrations. These data suggest that the CSF calbindin concentration is a sensitive biomarker of NPC1 disease that could be instrumental as an outcome measure of therapeutic efficacy in ongoing clinical trials.
- Received February 18, 2016.
- Accepted June 6, 2016.
This research was supported by the National Institutes of Health National Institute of Neurological Disorders and Stroke [Grant R01-NS073661], Support of Accelerated Research for NPC Disease, the Race for Adam Foundation, the National Niemann-Pick Disease Foundation, and the National Institutes of Health Office of the Director [Grant OD P40-10939 (all to C.V.)]; the Ara Parseghian Medical Research Foundation and the Dana’s Angels Research Trust [(to F.P. and C.V.)]; and the Intramural Research Programs of the National Institutes of Health Eunice Kennedy Shriver National Institute of Child Health and Human Development [(to F.P.)] and the National Heart, Lung, and Blood Institute [(to A.R.)].
- U.S. Government work not protected by U.S. copyright