Flunarizine rescues reduced lifespan in CLN3 triple knock-out Caenorhabditis elegans model of batten disease.
Flunarizine rescues reduced lifespan in CLN3 triple knock-out Caenorhabditis elegans model of batten disease.
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DOI：
10.1007/s10545-016-9986-1
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发表时间：
2017-03
影响因子：
4.2
通讯作者：
Bennett MJ
中科院分区：
文献类型：
--
作者：
Kwon YJ;Falk MJ;Bennett MJ
CLN 3病（Spielmeyer-Vogt-Sjogren-Batten病，以前称为经典的青少年神经元蜡样质脂褐质沉积症，NCL）是一种儿科发病的进行性神经退行性疾病，其特征为进行性视力丧失、癫痫发作、认知和运动功能丧失以及早期死亡。虽然尚不清楚精确的生化机制或疗法，但CLN 3疾病的发病机制涉及细胞内钙积聚，这可能引发细胞凋亡。我们先前在CLN 3缺陷的体外细胞模型中的工作表明，FDA批准的钙通道拮抗剂可能具有治疗价值。为了进一步评估这种方法在其他不可治疗的疾病中的潜在功效，我们试图比较CLN 3疾病动物模型中的治疗效果和潜在机制。在这里，我们使用了充分表征的XT 7完全cln-3敲除的C. elegans的细胞中的细胞毒性，以评估钙通道拮抗剂疗法在活的Batten病动物模型中的治疗功效。评价了五种钙通道拮抗剂对XT 7动物寿命和体内线粒体生理学的治疗效果。值得注意的是，在该模型动物中观察到1 μM氟桂利嗪的最大治疗效果，该浓度与先前在基于细胞的CLN 3疾病神经元模型中鉴定的浓度相同。具体而言，氟桂利嗪挽救了XT 7蠕虫的短寿命，并防止其病理生理线粒体积累。这些结果证实了氟桂利嗪在转化模式生物中cln-3疾病中的治疗功效和剂量。现在需要在CLN 3人类患者中进行临床治疗试验，以测试氟桂利嗪在患有这种无法治疗且最终致命的神经系统疾病的个体中的给药方案和疗效。
CLN3 disease (Spielmeyer-Vogt-Sjogren-Batten disease, previously known as classic juvenile neuronal ceroid lipofuscinosis, NCL) is a pediatric-onset progressive neurodegenerative disease characterized by progressive vision loss, seizures, loss of cognitive and motor function, and early death. While no precise biochemical mechanism or therapies are known, the pathogenesis of CLN3 disease involves intracellular calcium accumulation that may trigger apoptosis. Our prior work in in vitro cell models of CLN3 deficiency suggested that FDA-approved calcium channel antagonists may have therapeutic value. To further evaluate the potential efficacy of this approach in an otherwise untreatable disorder, we sought to compare the therapeutic effects and underlying mechanisms in an animal model of CLN3 disease. Here, we used the well-characterized XT7 complete cln-3 knockout strain of C. elegans to evaluate the therapeutic efficacy of calcium channel antagonist therapy in a living animal model of Batten disease. Therapeutic effects of five calcium channel antagonists were evaluated on XT7 animal lifespan and in vivo mitochondrial physiology. Remarkably, maximal therapeutic efficacy in this model animal was observed with 1 μM flunarizine, the identical concentration previously identified in cell-based neuronal models of CLN3 disease. Specifically, flunarizine rescued the short lifespan of XT7 worms and prevented their pathophysiologic mitochondrial accumulation. These results confirm the treatment efficacy and dosing of flunarizine in cln-3 disease in a translational model organism. Clinical treatment trials in CLN3 human patients are now needed to test the dosing regimen and efficacy of flunarizine in individuals suffering with this otherwise untreatable and ultimately lethal neurologic disease.