Bradbury Allison, Bagel Jessica, Sampson Maureen, Farhat Nicole, Ding Wenge, Swain Gary, Prociuk Maria, O'Donnell Patricia, Drobatz Kenneth, Gurda Brittney, Wassif Christopher, Remaley Alan, Porter Forbes, Vite Charles
Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania (A.B., J.B., W.D., G.S., M.P., P.O., K.D., B.G., C.V.); Division of Intramural Research, National Institutes of Health National Heart, Lung, and Blood Institute, Bethesda, Maryland (M.S., A.R.); and Division of Translational Research, National Institutes of Health Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland (N.F., C.W., F.P.)
Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania (A.B., J.B., W.D., G.S., M.P., P.O., K.D., B.G., C.V.); Division of Intramural Research, National Institutes of Health National Heart, Lung, and Blood Institute, Bethesda, Maryland (M.S., A.R.); and Division of Translational Research, National Institutes of Health Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland (N.F., C.W., F.P.).
J Pharmacol Exp Ther. 2016 Aug;358(2):254-61. doi: 10.1124/jpet.116.232975. Epub 2016 Jun 15.
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.
尼曼-匹克C型（NPC）1病是一种罕见的遗传性神经退行性疾病。2-羟丙基-β-环糊精（HPβCD）在动物模型中的治疗效果有明确证据，这促使在2013年启动了一项I/IIa期临床试验，并在2015年启动了一项IIb/III期试验。随着临床试验的进行，验证一种生物标志物以追踪疾病进展并作为治疗效果的辅助结局指标已成为必需。在本研究中，我们评估了脑脊液（CSF）中钙结合蛋白钙结合蛋白D-28K（钙结合蛋白）的浓度作为NPC1病的生物标志物。在自然发生的猫模型中，CSF钙结合蛋白在3周龄时显著升高，此时小脑功能障碍尚未出现，并在疾病终末期稳步增加至超过正常水平的10倍。在神经功能障碍发作之前开始每两周鞘内注射HPβCD，在随访至78周龄时，在所有分析的时间点，NPC1猫的CSF钙结合蛋白完全恢复正常。在临床症状出现后（16周龄）开始使用HPβCD导致CSF中钙结合蛋白水平延迟降低。对NPC1患者的CSF评估显示，与从未受影响患者收集的CSF样本相比，钙结合蛋白浓度显著升高。用鞘氨醇糖脂生物合成抑制剂米格列醇对NPC1患者进行标签外治疗，与治疗前浓度相比，CSF钙结合蛋白显著降低。这些数据表明，CSF钙结合蛋白浓度是NPC1病的一种敏感生物标志物，在正在进行的临床试验中作为治疗效果的结局指标可能有用。
