A roadmap to ALS prevention: strategies and priorities.
A roadmap to ALS prevention: strategies and priorities.
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DOI：
10.1136/jnnp-2022-330473
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发表时间：
2023-05
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--
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肌萎缩侧索硬化症（ALS）通常被认为是一种相对罕见的疾病，但风险估计表明，到85岁时，ALS的终生风险男性为1：263，女性为1：417。1迄今为止的治疗努力未能有效减缓疾病进展或延长生存期。这可能，至少部分地，反映了治疗通常是在疾病过程的后期开始的，此时损害可能已经太晚而无法逆转。事实上，一些证据表明，早期治疗可能会产生更好的结果。这些观察结果促使人们重新评估治疗ALS的潜在方法，并转向预防ALS的积极策略。实现预防ALS的宏伟目标需要大量的知识，包括了解ALS的原因和风险因素。它还需要确定一个机会窗口来研究那些有疾病风险的人，预测ALS临床表现何时出现的方法，以及通过在临床表现ALS出现之前减轻风险或治疗疾病的潜在生物学来干预的可行策略。在一小部分人群中已经取得了重大进展，这些人群由于携带高度渗透性ALS引起的基因突变而具有明显升高的ALS 4遗传风险。当疾病的原因是已知的，例如，遗传原因，有可能识别和研究症状前基因突变携带者。5此外，生物标志物，特别是神经丝轻链（NfL），已被确定为预测即将发生的表型转化的风险，6 7和针对疾病的根本原因的实验治疗已经开始出现。8 9这些因素的汇合促进了有史以来第一次ALS预防试验（NCT 04856982）的启动，该试验是在与快速进展的ALS相关的高度渗透性SOD1突变的携带者中进行的。在这项研究中，NfL水平每月监测一次，当NfL水平上升到预定阈值以上时，合格的症状前患者随机接受tofersen（一种SOD1反义寡核苷酸）或安慰剂。该试验的目标是延迟，甚至可能预防临床表现的ALS的出现。
Amyotrophic lateral sclerosis (ALS) is often considered a relatively rare disease, but risk estimates suggest that the lifetime risk of ALS is 1: 263 for males and 1: 417 for females by age 85. 1 Therapeutic efforts to date have failed to meaningfully slow disease progression or prolong survival. This may, at least in part, reflect that treatment is typically initiated late in the disease process, when damage may already be too advanced to reverse. Indeed, some evidence suggests that earlier treatment may yield better outcomes. 2 3 These observations prompt a reassessment of potential approaches for treating ALS, with a shift towards a proactive strategy for preventing ALS. 4 Achieving the ambitious goal of preventing ALS requires a large body of knowledge, including an understanding of the causes and risk factors for ALS. It also requires identifying a window of opportunity to study those at risk for disease, methods for predicting when the clinical manifestations of ALS will emerge, and viable strategies to intervene by mitigating risk or treating the underlying biology of disease before clinically manifest ALS emerges. Significant progress has already been made in a small subset of the population, which is at markedly elevated genetic risk for ALS 4 by harbouring highly penetrant ALS-causing gene mutations. When the cause of disease is known, for example, genetic cause, it is possible to identify and study presymptomatic gene mutation carriers. 5 Moreover, biomarkers, notably, neurofilament light chain (NfL), have been identified that predict the risk of imminent phenoconversion, 6 7 and experimental therapeutics that target the underlying cause of disease have begun to emerge. 8 9 This confluence of factors has facilitated the launch of the first-ever ALS prevention trial (NCT04856982) of a genetic therapy, tofersen, in carriers of highly penetrant SOD1 mutations, which are associated with rapidly progressive ALS. 10 In this study, NfL levels are monitored monthly, and eligible presymptomatic people randomised to receive tofersen (an SOD1 antisense oligonucleotide) or placebo when NfL levels rise above a predefined threshold. The goal of the trial is to delay, or possibly even prevent, the emergence of clinically manifest ALS.
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影响因子：
3.7
作者：
Beard JD;Engel LS;Richardson DB;Gammon MD;Baird C;Umbach DM;Allen KD;Stanwyck CL;Keller J;Sandler DP;Schmidt S;Kamel F
通讯作者：
Kamel F
DOI：
10.1093/brain/awab404
发表时间：
2022-03-29
期刊：
Brain : a journal of neurology
影响因子：
--
作者：
Benatar M;Wuu J;McHutchison C;Postuma RB;Boeve BF;Petersen R;Ross CA;Rosen H;Arias JJ;Fradette S;McDermott MP;Shefner J;Stanislaw C;Abrahams S;Cosentino S;Andersen PM;Finkel RS;Granit V;Grignon AL;Rohrer JD;McMillan CT;Grossman M;Al-Chalabi A;Turner MR;First International Pre-Symptomatic ALS Workshop
通讯作者：
First International Pre-Symptomatic ALS Workshop
DOI：
10.1016/s1474-4422(14)70219-4
发表时间：
2014-11
期刊：
The Lancet. Neurology
影响因子：
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Pearce N
肌萎缩性侧硬化症的疾病改良和有症状治疗。
影响因子：
5.9
作者：
Dorst J;Ludolph AC;Huebers A
通讯作者：
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影响因子：
2.1
作者：
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通讯作者：
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