Sha Sharon J, Miller Zachary A, Min Sang-Won, Zhou Yungui, Brown Jesse, Mitic Laura L, Karydas Anna, Koestler Mary, Tsai Richard, Corbetta-Rastelli Chiara, Lin Sophie, Hare Emma, Fields Scott, Fleischmann Kirsten E, Powers Ryan, Fitch Ryan, Martens Lauren Herl, Shamloo Mehrdad, Fagan Anne M, Farese Robert V, Pearlman Rodney, Seeley William, Miller Bruce L, Gan Li, Boxer Adam L
Memory and Aging Center, Department of Neurology, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA.
Gladstone Institute of Neurodegenerative Disease, San Francisco, CA.
Alzheimers Dement (N Y). 2017 Sep 12;3(4):507-512. doi: 10.1016/j.trci.2017.08.002. eCollection 2017 Nov.
Frontotemporal lobar degeneration-causing mutations in the progranulin () gene reduce progranulin protein (PGRN) levels, suggesting that restoring PGRN in mutation carriers may be therapeutic. Nimodipine, a Food and Drug Administration-approved blood-brain barrier-penetrant calcium channel blocker, increased PGRN levels in PGRN-deficient murine models. We sought to assess safety and tolerability of oral nimodipine in human mutation carriers.
We performed an open-label, 8-week, dose-finding, phase 1 clinical trial in eight mutation carriers to assess the safety and tolerability of nimodipine and assayed fluid and radiologic markers to investigate therapeutic endpoints.
There were no serious adverse events; however, PGRN concentrations (cerebrospinal fluid and plasma) did not change significantly following treatment (percent changes of -5.2 ± 10.9% in plasma and -10.2 ± 7.8% in cerebrospinal fluid). Measurable atrophy within the left middle frontal gyrus was observed over an 8-week period.
While well tolerated, nimodipine treatment did not alter PGRN concentrations or secondary outcomes.
颗粒前体蛋白（）基因中导致额颞叶变性的突变会降低颗粒前体蛋白（PGRN）水平，这表明恢复突变携带者体内的PGRN水平可能具有治疗作用。尼莫地平是一种经美国食品药品监督管理局批准的可穿透血脑屏障的钙通道阻滞剂，它能提高PGRN缺陷小鼠模型中的PGRN水平。我们旨在评估口服尼莫地平对携带人类突变者的安全性和耐受性。
我们对8名携带突变者进行了一项开放标签、为期8周的剂量探索性1期临床试验，以评估尼莫地平的安全性和耐受性，并检测液体和影像学标志物以研究治疗终点。
未出现严重不良事件；然而，治疗后PGRN浓度（脑脊液和血浆）没有显著变化（血浆中变化百分比为-5.2±10.9%，脑脊液中为-10.2±7.8%）。在8周的时间里观察到左侧额中回出现了可测量的萎缩。
虽然尼莫地平耐受性良好，但治疗并未改变PGRN浓度或次要结局。
