3rd Neurology Unit and ALS Centre, IRCCS 'Carlo Besta' Neurological Institute, Milan, Italy.
Scientific Direction, IRCCS 'Carlo Besta' Neurological Institute, Milan, Italy.
BMJ Open. 2017 Aug 11;7(8):e015434. doi: 10.1136/bmjopen-2016-015434.
Recent studies suggest that endoplasmic reticulum stress may play a critical role in the pathogenesis of amyotrophic lateral sclerosis (ALS) through an altered regulation of the proteostasis, the cellular pathway-balancing protein synthesis and degradation. A key mechanism is thought to be the dephosphorylation of eIF2α, a factor involved in the initiation of protein translation. Guanabenz is an alpha-2-adrenergic receptor agonist safely used in past to treat mild hypertension and is now an orphan drug. A pharmacological action recently discovered is its ability to modulate the synthesis of proteins by the activation of translational factors preventing misfolded protein accumulation and endoplasmic reticulum overload. Guanabenz proved to rescue motoneurons from misfolding protein stress both in in vitro and in vivo ALS models, making it a potential disease-modifying drug in patients. It is conceivable investigating whether its neuroprotective effects based on the inhibition of eIF2α dephosphorylation can change the progression of ALS.
Protocolised Management In Sepsis is a multicentre, randomised, double-blind, placebo-controlled phase II clinical trial with futility design. We will investigate clinical outcomes, safety, tolerability and biomarkers of neurodegeneration in patients with ALS treated with guanabenz or riluzole alone for 6 months. The primary aim is to test if guanabenz can reduce the proportion of patients progressed to a higher stage of disease at 6 months compared with their baseline stage as measured by the ALS Milano-Torino Staging (ALS-MITOS) system and to the placebo group. Secondary aims are safety, tolerability and change in at least one biomarker of neurodegeneration in the guanabenz arm compared with the placebo group. Findings will provide reliable data on the likelihood that guanabenz can slow the course of ALS in a phase III trial.
The study protocol was approved by the Ethics Committee of IRCCS 'Carlo Besta Foundation' of Milan (Eudract no. 2014-005367-32 Pre-results) based on the Helsinki declaration.
最近的研究表明，内质网应激可能通过改变蛋白质稳态的调节在肌萎缩侧索硬化症（ALS）的发病机制中发挥关键作用，细胞通路平衡蛋白质合成和降解。一个关键机制被认为是 eIF2α 的去磷酸化，这是参与蛋白质翻译起始的一个因素。胍法辛是一种过去安全用于治疗轻度高血压的α-2 肾上腺素能受体激动剂，现在是一种孤儿药。最近发现的一种药理作用是，它能够通过激活翻译因子来调节蛋白质的合成，防止错误折叠的蛋白质积累和内质网过载。胍法辛已被证明可在体外和体内 ALS 模型中挽救运动神经元免受错误折叠蛋白应激，使其成为患者潜在的疾病修饰药物。可以想象，研究其基于抑制 eIF2α 去磷酸化的神经保护作用是否可以改变 ALS 的进展。
脓毒症的方案化管理是一项多中心、随机、双盲、安慰剂对照的 II 期临床试验，采用无效性设计。我们将研究胍法辛或利鲁唑单独治疗 6 个月后 ALS 患者的临床结局、安全性、耐受性和神经退行性变的生物标志物。主要目的是测试胍法辛是否可以降低与基线相比，在 6 个月时进展到更高疾病阶段的患者比例，这是通过 ALS 米兰-都灵分期（ALS-MITOS）系统测量的，以及与安慰剂组相比。次要目标是比较胍法辛组与安慰剂组的安全性、耐受性和至少一种神经退行性变生物标志物的变化。研究结果将为胍法辛在 III 期试验中可能减缓 ALS 进程的可能性提供可靠数据。
该研究方案得到了米兰的 IRCCS 'Carlo Besta 基金会'伦理委员会的批准（Eudract 编号：2014-005367-32 预结果），基于赫尔辛基宣言。
