Phase 1 Study of a Sulforaphane-Containing Broccoli Sprout Homogenate for Sickle Cell Disease
Phase 1 Study of a Sulforaphane-Containing Broccoli Sprout Homogenate for Sickle Cell Disease
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DOI：
10.1371/journal.pone.0152895
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发表时间：
2016-04-12
期刊：
影响因子：
3.7
通讯作者：
Chi, Jen-Tsan
中科院分区：
文献类型：
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作者：
Doss, Jennifer F.;Jonassaint, Jude C.;Chi, Jen-Tsan
镰状细胞病(SCD)是世界上最常见的遗传性血红蛋白病。我们先前的结果表明，镰状红细胞氧化应激能力的降低可能是由于氧化应激调节因子NRF2(核因子(红系2)样蛋白2)的表达减少所致。我们发现，用萝卜硫素(SFN)激活红系祖细胞中的NRF2，显著增加了NRF2靶标Hmox1、NQO1和HBG1(胎儿血红蛋白亚单位)的表达，并呈剂量依赖性。因此，我们推测用SFN激活NRF2可能通过恢复氧化能力和增加胎儿血红蛋白浓度为SCD患者提供治疗益处。为了验证这一假设，我们对患有SCD的成年人进行了一项第一阶段的开放标记剂量递增研究，该研究包含在自然含有SFN的西兰花芽匀浆(BSH)中。主要研究终点和次要研究终点分别是对NRF2激活的安全性和生理性反应。我们发现BSH耐受性良好，在试验期间发生的少数不良事件可能与BSH的摄入无关。我们观察到在BSH治疗的最后一天，与治疗前相比，NRF2靶标Hmox1的平均相对全血mRNA水平增加(p=0.02)。我们还观察到从基线到治疗结束，NRF2靶标HBG1的平均相对mRNA水平有上升的趋势(p=0.10)，但HBF蛋白没有显著变化。我们得出结论，在所提供的剂量下，BSH对稳定的SCD患者是安全的，并可能诱导基因表达水平的变化。因此，我们建议研究更有效的NRF2诱导剂，这可能会引发更强劲的生理变化，并为SCD患者提供临床益处。
Sickle cell disease (SCD) is the most common inherited hemoglobinopathy worldwide. Our previous results indicate that the reduced oxidative stress capacity of sickle erythrocytes may be caused by decreased expression of NRF2 (Nuclear factor (erythroid-derived 2)-like 2), an oxidative stress regulator. We found that activation of NRF2 with sulforaphane (SFN) in erythroid progenitors significantly increased the expression of NRF2 targets HMOX1, NQO1, and HBG1 (subunit of fetal hemoglobin) in a dose-dependent manner. Therefore, we hypothesized that NRF2 activation with SFN may offer therapeutic benefits for SCD patients by restoring oxidative capacity and increasing fetal hemoglobin concentration. To test this hypothesis, we performed a Phase 1, open-label, dose-escalation study of SFN, contained in a broccoli sprout homogenate (BSH) that naturally contains SFN, in adults with SCD. The primary and secondary study endpoints were safety and physiological response to NRF2 activation, respectively. We found that BSH was well tolerated, and the few adverse events that occurred during the trial were not likely related to BSH consumption. We observed an increase in the mean relative whole blood mRNA levels for the NRF2 target HMOX1 (p = 0.02) on the last day of BSH treatment, compared to pre-treatment. We also observed a trend toward increased mean relative mRNA levels of the NRF2 target HBG1 (p = 0.10) from baseline to end of treatment, but without significant changes in HbF protein. We conclude that BSH, in the provided doses, is safe in stable SCD patients and may induce changes in gene expression levels. We therefore propose investigation of more potent NRF2 inducers, which may elicit more robust physiological changes and offer clinical benefits to SCD patients.