Background: Amyotrophic lateral sclerosis (ALS) is a rapidly progressive fatal neurodegenerative condition. There are no effective treatments. The only globally licensed medication, that prolongs life by 2–3 months, was approved by the FDA in 1995. One reason for the absence of effective treatments is disease heterogeneity noting that ALS is clinically heterogeneous and can be considered to exist on a neuropathological spectrum with frontotemporal dementia. Despite this significant clinical heterogeneity, protein misfolding has been identified as a unifying pathological feature in these cases. Based on this shared pathophysiology, we carried out a systematic review and meta-analysis to assess the therapeutic efficacy of compounds that specifically target protein misfolding in preclinical studies of both ALS and FTD. Methods: Three databases: (i) PubMed, (ii) MEDLINE, and (iii) EMBASE were searched. All studies comparing the effect of treatments targeting protein misfolding in pre-clinical ALS or FTD models to a control group were retrieved. Results: Systematic review identified 70 pre-clinical studies investigating the effects of therapies targeting protein misfolding on survival. Meta-analysis revealed that targeting protein misfolding did significantly improve survival compared to untreated controls (p < 0.001, df = 68, α = 0.05, CI 1.05–1.16), with no evidence of heterogeneity between studies (I2 = 0%). Further subgroup analyses, evaluating the effect of timing of these interventions, showed that, only treating prior to symptom onset (n = 33), significantly improved survival (p < 0.001, df = 31, α = 0.05, CI 1.08–1.29), although this likely reflects the inadequate sample size of later time points. Furthermore, arimoclomol was found to significantly reduce secondary outcome measures including: (i) histological outcomes, (ii) behavioral outcomes, and (iii) biochemical outcomes (p < 0.005). Conclusions: This analysis supports the hypothesis that protein misfolding plays an important role in the pathogenesis of ALS and FTD and that targeting protein misfolding, at least in pre-clinical models, can significantly improve survival, especially if such an intervention is administered prior to symptom onset.

中文翻译：

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肌萎缩侧索硬化蛋白稳态的治疗靶向——临床前研究的系统评价和荟萃分析

背景：肌萎缩侧索硬化 (ALS) 是一种快速进展的致命神经退行性疾病。没有有效的治疗方法。唯一一种可延长 2-3 个月寿命的全球许可药物，于 1995 年获得 FDA 批准。 缺乏有效治疗方法的一个原因是疾病异质性，注意到 ALS 在临床上具有异质性，可以被认为存在于神经病理谱中患有额颞叶痴呆。尽管存在这种显着的临床异质性，但蛋白质错误折叠已被确定为这些病例的统一病理特征。基于这一共同的病理生理学，我们进行了系统评价和荟萃分析，以评估专门针对蛋白质错误折叠的化合物在 ALS 和 FTD 的临床前研究中的治疗效果。方法： 三个数据库：(i) PubMed、(ii) MEDLINE 和 (iii) EMBASE 被搜索。检索了将临床前 ALS 或 FTD 模型中靶向蛋白质错误折叠的治疗效果与对照组进行比较的所有研究。结果：系统审查确定了 70 项临床前研究，这些研究调查了针对蛋白质错误折叠的疗法对存活率的影响。荟萃分析显示，与未治疗的对照相比，靶向蛋白质错误折叠确实显着提高了生存率（p < 0.001，df = 68，α = 0.05，CI 1.05–1.16），研究之间没有异质性的证据（I2 = 0%）。进一步的亚组分析评估了这些干预措施的时机影响，结果表明，仅在症状出现前进行治疗（n = 33），显着提高了生存率（p < 0.001，df = 31，α = 0.05，CI 1.08–1.29），尽管这可能反映了后期时间点的样本量不足。此外，发现阿莫氯醇可显着降低次要结果指标，包括：(i) 组织学结果、(ii) 行为结果和 (iii) 生化结果 (p < 0.005)。结论：该分析支持以下假设：蛋白质错误折叠在 ALS 和 FTD 的发病机制中起重要作用，并且靶向蛋白质错误折叠，至少在临床前模型中，可以显着提高存活率，尤其是如果在出现症状之前进行此类干预发作。