检索问题
"肌萎缩侧索硬化最新治疗进展 2024-2025"
关于2024-2025年肌萎缩侧索硬化（渐冻症）最新治疗进展的报告
2024年至2025年，渐冻症（ALS）的治疗格局正在经历一场从“无法治愈”向“精准打击”转变的历史性跨越。目前最核心的突破在于基因疗法的落地，特别是针对特定基因突变（如 SOD1）的药物不仅获批上市，还显示出能延缓疾病进程的潜力；与此同时，针对更广泛患者群体的免疫疗法和细胞疗法也在紧锣密鼓地研发中。 虽然目前仍未找到能彻底治愈所有类型渐冻症的“万能药”，但我们已经拥有了能精准修补某些“基因漏洞”的武器，并且在改善患者生存质量（如吞咽和呼吸功能）方面取得了实质性进展。
以下是这一领域的详细进展解读：
一、 基因疗法的里程碑：精准修复“生命图纸”
对于一部分渐冻症患者来说，生病的原因是身体里的“建筑图纸”（基因）打印错了，导致生产出有毒的蛋白质，毒死了运动神经元。最新的疗法正是为了修正这些错误。
1. Tofersen（Qalsody）：针对 SOD1 突变的“特种兵” 这是目前最令人振奋的消息。Tofersen 是首个针对 SOD1 基因突变引起的渐冻症的获批药物（已获FDA和EMA批准）。
- 它的原理：你可以把 SOD1 基因突变想象成一个不断产生“垃圾蛋白”的工厂。Tofersen 是一种反义寡核苷酸（ASO）药物，它就像是一张“封条”，专门贴在错误的图纸上，让工厂停止生产这种有毒的蛋白，从而让神经细胞喘口气 。
- 名词解释：反义寡核苷酸（ASO） —— 这听起来很复杂，其实它就像是一段专门设计好的“短代码”。当身体里的基因试图根据错误指令制造有害物质时，这段短代码会精准地与错误指令结合，像拉链一样锁住它，阻止它发挥作用，从而被身体清理掉。
- 临床效果：多项研究和临床试验显示，使用 Tofersen 后，患者脑脊液中的 SOD1 蛋白水平显著下降，血液中的神经丝轻链蛋白（NfL） 也明显减少 。
- 名词解释：神经丝轻链蛋白（NfL） —— 这是一个衡量神经损伤程度的“晴雨表”。神经细胞就像电线，NfL 是包裹在电线外面的绝缘皮碎片。如果血液里检测到很多 NfL，说明很多神经细胞破损了。Tofersen 能降低 NfL 水平，意味着它能有效减少神经细胞的死亡 。
- 长期获益：虽然早期的短期试验数据在减缓功能衰退上只差一点点没达到统计学意义，但后续的长期观察（延续至108周，即2年多）发现，越早开始治疗，效果越好。部分患者的病情甚至趋于稳定，呼吸功能和肌肉力量的衰退速度明显慢于安慰剂组 。一项包含12个研究的分析显示，使用 Tofersen 的患者病情进展速度显著降低 。
2. 针对 C9orf72 和 FUS 基因的探索：挑战更难的高峰 除了 SOD1，科学家也在攻克其他基因突变：
- C9orf72 基因：这是导致遗传性渐冻症最常见的原因。不幸的是，之前一款针对该基因的药物（BIIB078）临床试验失败了，虽然药物成功进入了大脑，但没能改善症状，反倒可能干扰了正常的免疫反应 。这提醒我们，仅仅把药送进脑子里还不够，还得找对靶点。目前，科学家正在转向针对该基因DNA层面的新疗法 。另一种药物 Apilimod dimesylate 在早期临床试验（2a期）中表现出了很好的安全性，并成功降低了有毒蛋白的水平，为这类患者带来了新希望 。
- FUS 基因：这是一种导致青少年或年轻成人快速发病的凶险突变。针对 FUS 的基因沉默疗法（类似于 Tofersen 的原理）目前正在研发中，旨在通过脊髓注射药物来减少有毒蛋白的产生 。
二、 对症治疗与生存质量：让生活更有尊严
除了针对病根，如何让患者在带病生存期间活得更舒服、更有尊严，也是2024-2025年的关注重点。
1. 改善吞咽与言语功能 很多渐冻症患者会因为延髓症状（控制说话和吞咽的神经受损）而出现吞咽困难和口水控制不住流出的尴尬情况。
- 名词解释：延髓症状 —— 延髓是大脑和脊髓连接的地方，负责指挥舌头、喉咙和嘴巴的肌肉。一旦这里受损，人就会说话含糊不清（构音障碍）、喝水呛咳（吞咽困难）或控制不住流口水。
- Nuedexta（右美沙芬/奎尼丁组合）：这原本是一种治疗情绪失控（如强哭强笑）的药，但最新的临床观察发现，它似乎也能改善患者的吞咽和说话功能。它通过保护脑干的运动神经元，可能对那些有吞咽困难的患者有帮助，哪怕他们没有情绪失控的问题 。这是一个“老药新用”的典型例子。
2. 营养与呼吸管理 最新的管理指南强调，吞咽困难（Dysphagia） 和 流涎症（Sialorrhea） 必须在每次就诊时进行评估 。
- 如果患者吃不下东西，尽早讨论使用经皮内镜下胃造瘘术（PEG）（就是在肚子上留个小孔直接喂食）非常重要，这不仅能保证营养，还能避免食物呛进肺里引发肺炎 。
- 保持高热量饮食也被证明对延缓病情有一定帮助 。
三、 探索中的新战场：免疫调节与干细胞
科学家们意识到，渐冻症不仅仅是神经元自己的问题，身体里的免疫系统可能也成了“帮凶”。
1. 免疫疗法：安抚“发火”的免疫细胞 在大脑和脊髓里，有一种叫小胶质细胞（Microglia） 的免疫卫士。在渐冻症中，这些卫士“杀红了眼”，不仅攻击病毒，还开始攻击自身的神经元。
- 场景理解：这就好比警察原本是抓坏人的，但在混乱中，警察过度紧张，开始误伤平民。免疫疗法的目的就是让这些“警察”冷静下来，或者调节它们的巡逻方式 。目前针对调节小胶质细胞和T细胞的疗法正在多项神经退行性疾病中进行测试 。
2. 干细胞疗法：不仅是“缺啥补啥” 干细胞疗法并不只是简单地种出新的神经元来替代死的神经元（这在大脑里非常难），目前更多是利用干细胞来分泌神经营养因子，像“施肥”一样保护现存的神经元，延缓它们死亡 。这一领域虽然充满希望，但仍在不断优化以提高临床效果。
四、 未来的方向：生物标志物与极早期干预
过去，医生往往要等患者出现明显手脚无力时才能确诊，这时神经元往往已经死了一大半。现在的趋势是“治未病”。
- 神经丝轻链蛋白（NfL） 的应用不仅用于判断药效，还被用于预测风险。对于有家族遗传史的人，如果在发病前就检测到 NfL 升高，可能意味着神经破坏已经悄悄开始，这为在症状出现前就使用 Tofersen 等药物提供了依据 。
- 这种“预防性治疗”的理念正在改变渐冻症的临床实践，目标是将疾病扼杀在萌芽状态，或者至少让它变成一种像糖尿病一样可控的慢性病 。
总结
2024-2025年的渐冻症治疗不再是一片黑暗。Tofersen 的成功证明了基因疗法是可行的，为特定基因突变的患者打开了生存之门。对于更广泛的患者，虽然尚未有治愈良方，但NfL等生物标志物的应用、Nuedexta等药物对症状的改善、以及正在进行的免疫和干细胞研究，都在一步步将防线前移。现在的治疗策略正从单一药物转向“鸡尾酒疗法”——结合基因修正、神经保护、免疫调节和营养支持，全方位地围堵疾病。
References
1Understanding Amyotrophic Lateral Sclerosis: Pathophysiology, Diagnosis, and Therapeutic Advances.PubMed
Radu Eugen Rizea, Antonio-Daniel Corlatescu, Horia Petre Costin, et al.
Int J Mol Sci. 2024 Sep 15;25(18):9966. doi: 10.3390/ijms25189966.
This review offers an in-depth examination of amyotrophic lateral sclerosis (ALS), addressing its epidemiology, pathophysiology, clinical presentation, diagnostic techniques, and current as well as emerging treatments. The purpose is to condense key findings and illustrate the complexity of ALS, which is shaped by both genetic and environmental influences. We reviewed the literature to discuss recent advancements in understanding molecular mechanisms such as protein misfolding, mitochondrial dysfunction, oxidative stress, and axonal transport defects, which are critical for identifying potential therapeutic targets. Significant progress has been made in refining diagnostic criteria and identifying biomarkers, leading to earlier and more precise diagnoses. Although current drug treatments provide some benefits, there is a clear need for more effective therapies. Emerging treatments, such as gene therapy and stem cell therapy, show potential in modifying disease progression and improving the quality of life for ALS patients. The review emphasizes the importance of continued research to address challenges such as disease variability and the limited effectiveness of existing treatments. Future research should concentrate on further exploring the molecular foundations of ALS and developing new therapeutic approaches. The implications for clinical practice include ensuring the accessibility of new treatments and that healthcare systems are equipped to support ongoing research and patient care.
2Update on recent advances in amyotrophic lateral sclerosis.PubMed
Nilo Riva, Teuta Domi, Laura Pozzi, et al.
J Neurol. 2024 Jul;271(7):4693-4723. doi: 10.1007/s00415-024-12435-9. Epub 2024 May 27.
In the last few years, our understanding of disease molecular mechanisms underpinning ALS has advanced greatly, allowing the first steps in translating into clinical practice novel research findings, including gene therapy approaches. Similarly, the recent advent of assistive technologies has greatly improved the possibility of a more personalized approach to supportive and symptomatic care, in the context of an increasingly complex multidisciplinary line of actions, which remains the cornerstone of ALS management. Against this rapidly growing background, here we provide an comprehensive update on the most recent studies that have contributed towards our understanding of ALS pathogenesis, the latest results from clinical trials as well as the future directions for improving the clinical management of ALS patients.
3The genetics of amyotrophic lateral sclerosis.PubMed
Melissa Nijs, Philip Van Damme
Curr Opin Neurol. 2024 Oct 1;37(5):560-569. doi: 10.1097/WCO.0000000000001294. Epub 2024 Aug 22.
PURPOSE OF REVIEW: Amyotrophic lateral sclerosis (ALS) has a strong genetic basis, but the genetic landscape of ALS appears to be complex. The purpose of this article is to review recent developments in the genetics of ALS. RECENT FINDINGS: Large-scale genetic studies have uncovered more than 40 genes contributing to ALS susceptibility. Both rare variants with variable effect size and more common variants with small effect size have been identified. The most common ALS genes are C9orf72 , SOD1 , TARDBP and FUS . Some of the causative genes of ALS are shared with frontotemporal dementia, confirming the molecular link between both diseases. Access to diagnostic gene testing for ALS has to improve, as effective gene silencing therapies for some genetic subtypes of ALS are emerging, but there is no consensus about which genes to test for. SUMMARY: Our knowledge about the genetic basis of ALS has improved and the first effective gene silencing therapies for specific genetic subtypes of ALS are underway. These therapeutic advances underline the need for better access to gene testing for people with ALS. Further research is needed to further map the genetic heterogeneity of ALS and to establish the best strategy for gene testing in a clinical setting.
4Tofersen for SOD1 ALS.PubMed
William H Everett, Robert C Bucelli
Neurodegener Dis Manag. 2024;14(5):149-160. doi: 10.1080/17582024.2024.2402216. Epub 2024 Sep 27.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative condition affecting the motor system. The heterogenous nature of ALS complicates trial design. Genetic forms of ALS present an opportunity to intervene in a less heterogeneous population. ALS associated with gain of function mutations in make 'knock-down' strategies an attractive therapeutic approach. Tofersen, an antisense oligonucleotide that reduces expression of SOD1 via RNAase mediated degradation of mRNA, has shown robust effects on ALS biomarkers. While a Phase III trial of tofersen failed to meet its primary end point, open label extension data suggests that tofersen slows progression of SOD1 ALS.
5Amyotrophic lateral sclerosis caused by hexanucleotide repeat expansions in C9orf72: from genetics to therapeutics.PubMed
Sarah Mizielinska, Guillaume M Hautbergue, Tania F Gendron, et al.
Lancet Neurol. 2025 Mar;24(3):261-274. doi: 10.1016/S1474-4422(25)00026-2.
GGGGCC repeat expansions in C9orf72 are a common genetic cause of amyotrophic lateral sclerosis in people of European ancestry; however, substantial variability in the penetrance of the mutation, age at disease onset, and clinical presentation can complicate diagnosis and prognosis. The repeat expansion is bidirectionally transcribed in the sense and antisense directions into repetitive RNAs and translated into dipeptide repeat proteins, and both accumulate in the cortex, cerebellum, and the spinal cord. Furthermore, neuropathological aggregates of phosphorylated TDP-43 are observed in motor cortex and other cortical regions, and in the spinal cord of patients at autopsy. C9orf72 repeat expansions can also cause frontotemporal dementia. The GGGGCC repeat induces a complex interplay of loss-of-function and gain-of-function pathological mechanisms. Clinical trials using antisense oligonucleotides to target the GGGGCC repeat RNA have not been successful, potentially because they only target a single gain-of-function mechanism. Novel therapeutic approaches targeting the DNA repeat expansion, multiple repeat-derived RNA species, or downstream targets of TDP-43 dysfunction are, however, on the horizon, together with the development of diagnostic and prognostic biomarkers.
6Updates on Disease Mechanisms and Therapeutics for Amyotrophic Lateral Sclerosis.PubMed
Lien Nguyen
Cells. 2024 May 21;13(11):888. doi: 10.3390/cells13110888.
Amyotrophic lateral sclerosis (ALS), or Lou Gehrig's disease, is a motor neuron disease. In ALS, upper and lower motor neurons in the brain and spinal cord progressively degenerate during the course of the disease, leading to the loss of the voluntary movement of the arms and legs. Since its first description in 1869 by a French neurologist Jean-Martin Charcot, the scientific discoveries on ALS have increased our understanding of ALS genetics, pathology and mechanisms and provided novel therapeutic strategies. The goal of this review article is to provide a comprehensive summary of the recent findings on ALS mechanisms and related therapeutic strategies to the scientific audience. Several highlighted ALS research topics discussed in this article include the 2023 FDA approved drug for ALS, the updated GGGGCC repeat-expansion-related mechanisms and therapeutic targets, TDP-43-mediated cryptic splicing and disease markers and diagnostic and therapeutic options offered by these recent discoveries.
7Amyotrophic Lateral Sclerosis: Pathophysiological Mechanisms and Treatment Strategies (Part 2).PubMed
Christina Tolochko, Olga Shiryaeva, Tatiana Alekseeva, et al.
Int J Mol Sci. 2025 May 29;26(11):5240. doi: 10.3390/ijms26115240.
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease associated with damage to motor neurons and leading to severe muscle weakness and, eventually, death. Over the past decade, understanding of the key pathogenetic links of ALS, including glutamate-mediated excitotoxicity and oxidative stress, has significantly advanced. This review considers the recent evidence on molecular mechanisms of these processes, as well as the therapeutic strategies aimed at their modulation. Special attention is paid to antiglutamatergic and antioxidant drugs as approaches to the ALS pathogenetic therapy.
8Tofersen for SOD1 amyotrophic lateral sclerosis: a systematic review and meta-analysis.PubMed
Abdullah Ashraf Hamad, Ibraheem M Alkhawaldeh, Abdulqadir J Nashwan, et al.
Neurol Sci. 2025 May;46(5):1977-1985. doi: 10.1007/s10072-025-07994-2. Epub 2025 Jan 17.
OBJECTIVE: Tofersen, an antisense oligonucleotide, has recently received FDA and EMA approval for treating amyotrophic lateral sclerosis (ALS) in adults with SOD1 gene mutations. This systematic review and meta-analysis synthesized evidence on tofersen's safety and efficacy in patients with SOD1-related ALS. METHODS: A comprehensive search of three databases was conducted from inception through October 2024. Eligible studies included clinical trials, observational studies, and case studies. Meta-analyses were conducted using a random-effects model in RevMan. RESULTS: Twelve studies involving 195 patients treated with tofersen met the inclusion criteria, comprising two randomized controlled trials (RCTs), five cohort studies, one case series, and four case reports. Tofersen demonstrated promising effects, notably reducing SOD1 levels in cerebrospinal fluid and neurofilament light chain (NfL) in plasma, a biomarker strongly correlated with ALS progression and survival. Meta-analysis of RCTs showed a significantly lower rate of decline in ALS Functional Rating Scale-Revised (ALSFRS-R) scores from baseline in the tofersen group compared to placebo (SMD = 0.44, 95% CI [0.05 to 0.83], P = 0.03) and a significant reduction in the decline of predicted Slow Vital Capacity (P = 0.005). In a pre-post meta-analysis of five studies, a significant decrease in ALS progression rate (ALSFRS-R decline rate) was observed (MD = -0.28, 95% CI [-0.40 to -0.15], P < 0.0001). Reported adverse events were consistent with ALS progression or procedural effects. CONCLUSION: Current evidence suggests that tofersen effectively reduces SOD1 and NfL levels and slow disease progression in SOD1 ALS, showing promise as a targeted therapeutic option.
9Current therapy in amyotrophic lateral sclerosis (ALS): A review on past and future therapeutic strategies.PubMed
Yuqing Wei, Sheng Zhong, Huajing Yang, et al.
Eur J Med Chem. 2024 Jun 5;272:116496. doi: 10.1016/j.ejmech.2024.116496. Epub 2024 May 16.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects the first and second motoneurons (MNs), associated with muscle weakness, paralysis and finally death. The exact etiology of the disease still remains unclear. Currently, efforts to develop novel ALS treatments which target specific pathomechanisms are being studied. The mechanisms of ALS pathogenesis involve multiple factors, such as protein aggregation, glutamate excitotoxicity, oxidative stress, mitochondrial dysfunction, apoptosis, inflammation etc. Unfortunately, to date, there are only two FDA-approved drugs for ALS, riluzole and edavarone, without curative treatment for ALS. Herein, we give an overview of the many pathways and review the recent discovery and preclinical characterization of neuroprotective compounds. Meanwhile, drug combination and other therapeutic approaches are also reviewed. In the last part, we analyze the reasons of clinical failure and propose perspective on the treatment of ALS in the future.
10Clinical features and progress in diagnosis and treatment of amyotrophic lateral sclerosis.PubMed
Dongxiang Yuan, Shishi Jiang, Renshi Xu
Ann Med. 2024 Dec;56(1):2399962. doi: 10.1080/07853890.2024.2399962. Epub 2024 Dec 3.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of the central nervous system. Despite a large number of studies, the current prognosis of ALS is still not ideal. This article briefly describes the clinical features including epidemiology, genetic structure and clinical manifestations, as well as the progress of new diagnostic criteria and treatment of ALS. Meanwhile, we also discussed further both developments and improvements to enhance understanding and accelerating the introduction of the effective treatments of ALS.
11Amyotrophic lateral sclerosis caused by FUS mutations: advances with broad implications.PubMed
Thomas G Moens, Sandrine Da Cruz, Manuela Neumann, et al.
Lancet Neurol. 2025 Feb;24(2):166-178. doi: 10.1016/S1474-4422(24)00517-9.
Autosomal dominant mutations in the gene encoding the DNA and RNA binding protein FUS are a cause of amyotrophic lateral sclerosis (ALS), and about 0·3-0·9% of patients with ALS are FUS mutation carriers. FUS-mutation-associated ALS (FUS-ALS) is characterised by early onset and rapid progression, compared with other forms of ALS. However, different pathogenic mutations in FUS can result in markedly different age at symptom onset and rate of disease progression. Most FUS mutations disrupt its nuclear localisation, leading to its cytoplasmic accumulation in the CNS. FUS also forms inclusions in around 5% of patients with the related neurodegenerative condition frontotemporal dementia. However, there are key differences between the two diseases at the genetic and neuropathological level, which suggest distinct pathogenic processes. Experimental models have uncovered potential pathogenic mechanisms in FUS-ALS and informed therapeutic strategies that are currently in development, including the silencing of FUS expression using an intrathecally administered antisense oligonucleotide.
12Narrative review of diagnosis, management and treatment of dysphagia and sialorrhea in amyotrophic lateral sclerosis.PubMed
Bogdan Bjelica, Susanne Petri
J Neurol. 2024 Oct;271(10):6508-6513. doi: 10.1007/s00415-024-12657-x. Epub 2024 Aug 29.
The degenerative motor neuron disorder amyotrophic lateral sclerosis (ALS) frequently leads bulbar symptoms like dysarthria, dysphagia, and sialorrhea, in approximately one-third of cases being the initial symptom. Throughout the disease, more than two-thirds of ALS patients experience dysphagia, regardless of the region of onset. In this review, we aimed to offer an updated overview of dysphagia and sialorrhea in ALS, covering its diagnosis, monitoring, and treatment in clinical practice. Regular assessment of dysphagia and sialorrhea during each patient visit is essential and should be a standard aspect of ALS care. Early discussion of potential treatments such as high-calorie diets or percutaneous endoscopic gastrostomy (PEG) is crucial. Furthermore, this review highlights and discusses potential areas for improvement in both clinical practice and research.
13Molecular impact of antisense oligonucleotide therapy in C9orf72-associated ALS.PubMed
Zachary T McEachin, Mingee Chung, Sabrina A Stratton, et al.
Cell. 2025 Nov 13;188(23):6424-6435.e17. doi: 10.1016/j.cell.2025.07.045. Epub 2025 Aug 26.
C9orf72-associated amyotrophic lateral sclerosis (c9ALS) is caused by an intronic GC repeat expansion that leads to toxic RNA transcripts and dipeptide repeat proteins (DPRs). A clinical trial using the antisense oligonucleotide (ASO) BIIB078 to target these transcripts was discontinued after failing to provide clinical benefit. Here, we determine the extent of target engagement in the central nervous system (CNS) and elucidate pharmacodynamic cerebrospinal fluid (CSF) biomarkers following treatment. CSF from BIIB078-treated cases showed reduced DPRs and sustained increases in inflammatory biomarkers, including C-C motif chemokine ligand 26 (CCL26). BIIB078 was widely distributed in postmortem CNS tissue; however, DPRs and phosphorylated TDP-43 remained abundant. Proteomic signatures in c9ALS spinal cord were not altered with treatment, although a distinct increase in RNase T2 abundance that correlated with BIIB078 concentration was observed. Thus, despite widespread distribution, BIIB078 did not significantly impact key CNS pathologies, emphasizing the need to identify pharmacodynamic biomarkers that reflect disease-relevant neuropathological changes in response to ASO therapies.
14Tofersen: A Review in Amyotrophic Lateral Sclerosis Associated with SOD1 Mutations.PubMed
Aisling McGuigan, Hannah A Blair
CNS Drugs. 2025 Sep;39(9):903-912. doi: 10.1007/s40263-025-01204-5. Epub 2025 Jul 10.
Tofersen (QALSODY) is the first drug approved for the treatment of amyotrophic lateral sclerosis (ALS) associated with superoxide dismutase 1 (SOD1) mutations. Tofersen is an antisense oligonucleotide that induces SOD1 mRNA degradation. In the 28-week, placebo-controlled, multinational, phase III VALOR trial, intrathecally administered tofersen reduced plasma concentrations of neurofilament proteins (biomarker for neuro-axonal injury) and total SOD1 protein in cerebrospinal fluid in patients with SOD1 mutation-associated ALS. These reductions were sustained in a long-term, open-label extension study. The decline in functional outcomes was not significantly reduced with tofersen treatment compared with placebo in the 28-week phase III trial, although in the longer-term open-label study, early tofersen initiation was associated with slowed functional decline versus delayed tofersen initiation. Tofersen had an acceptable tolerability profile in clinical trials with a favourable benefit-to-risk balance. In summary, tofersen is a new disease-modifying therapy for patients with ALS attributed to an SOD1 mutation, offering reductions in levels of a biomarker associated with neurodegeneration and disease progression, with an acceptable tolerability profile.
15Apilimod dimesylate in C9orf72 amyotrophic lateral sclerosis: a randomized phase 2a clinical trial.PubMed
Suma Babu, Katharine A Nicholson, Jeffrey D Rothstein, et al.
Brain. 2024 Sep 3;147(9):2998-3008. doi: 10.1093/brain/awae109.
Apilimod dimesylate is a first-in-class phosphoinositide kinase, FYVE-type zinc finger-containing (PIKfyve) inhibitor with a favourable clinical safety profile and has demonstrated activity in preclinical C9orf72 and TDP-43 amyotrophic lateral sclerosis (ALS) models. In this ALS clinical trial, the safety, tolerability, CNS penetrance and modulation of pharmacodynamic target engagement biomarkers were evaluated. This phase 2a, randomized, double-blind, placebo-controlled, biomarker-end-point clinical trial was conducted in four US centres (ClinicalTrials.gov NCT05163886). Participants with C9orf72 repeat expansions were randomly assigned (2:1) to receive twice-daily oral treatment with 125 mg apilimod dimesylate capsules or matching placebo for 12 weeks, followed by a 12-week open-label extension. Safety was measured as the occurrence of treatment-emergent or serious adverse events attributable to the study drug and tolerability at trial completion or treatment over 12 weeks. Changes from baseline in plasma and CSF and concentrations of apilimod dimesylate and its active metabolites and of pharmacodynamic biomarkers of PIKfyve inhibition [soluble glycoprotein nonmetastatic melanoma protein B (sGPNMB) upregulation] and disease-specific CNS target engagement [poly(GP)] were measured. Between 16 December 2021 and 7 July 2022, 15 eligible participants were enrolled. There were no drug-related serious adverse events reported in the trial. Fourteen (93%) participants completed the double-blind period with 99% dose compliance [n = 9 (90%) apilimod dimesylate; n = 5 (100%) placebo]. At Week 12, apilimod dimesylate was measurable in CSF at 1.63 ng/ml [standard deviation (SD): 0.937]. At Week 12, apilimod dimesylate increased plasma sGPNMB by >2.5-fold (P < 0.001), indicating PIKfyve inhibition, and lowered CSF poly(GP) protein levels by 73% (P < 0.001), indicating CNS tissue-level proof of mechanism. Apilimod dimesylate met prespecified key safety and biomarker end-points in this phase 2a trial and demonstrated CNS penetrance and pharmacodynamic target engagement. Apilimod dimesylate was observed to result in the greatest reduction in CSF poly(GP) levels observed to date in C9orf72 clinical trials.
16Immune mechanisms and shared immune targets in neurodegenerative diseases.PubMed
Howard L Weiner
Nat Rev Neurol. 2025 Feb;21(2):67-85. doi: 10.1038/s41582-024-01046-7. Epub 2024 Dec 16.
The immune system plays a major part in neurodegenerative diseases. In some, such as multiple sclerosis, it is the primary driver of the disease. In others, such as Alzheimer disease, amyotrophic lateral sclerosis and Parkinson disease, it has an amplifying role. Immunotherapeutic approaches that target the adaptive and innate immune systems are being explored for the treatment of almost all neurological diseases, and the targets and approaches are often common across diseases. Microglia are the primary immune cells in the brain that contribute to disease pathogenesis, and are consequently a common immune target for therapy. Other therapeutic approaches target components of the peripheral immune system, such as regulatory T cells and monocytes, which in turn act within the CNS. This Review considers in detail how microglia, monocytes and T cells contribute to the pathogenesis of multiple sclerosis, Alzheimer disease, amyotrophic lateral sclerosis and Parkinson disease, and their potential as shared therapeutic targets across these diseases. The microbiome is also highlighted as an emerging therapeutic target that indirectly modulates the immune system. Therapeutic approaches being developed to target immune function in neurodegenerative diseases are discussed, highlighting how immune-based approaches developed to treat one disease could be applicable to multiple other neurological diseases.
17Amyotrophic lateral sclerosis caused by SOD1 variants: from genetic discovery to disease prevention.PubMed
Michael Benatar, Janice Robertson, Peter Munch Andersen
Lancet Neurol. 2025 Jan;24(1):77-86. doi: 10.1016/S1474-4422(24)00479-4.
Pathogenic variants in the superoxide dismutase 1 (SOD1) gene were the first identified genetic cause of amyotrophic lateral sclerosis (ALS), in 1993. This discovery enabled the development of transgenic rodent models for studying the biology of SOD1 ALS. The understanding that SOD1 ALS is driven by a toxic gain-of-function mutation has led to therapeutic strategies that aim to lower concentrations of SOD1 protein, an endeavour that has been complicated by the phenotypic heterogeneity of SOD1 ALS. The successful development of genetically targeted therapies to reduce SOD1 expression, together with a better understanding of pre-symptomatic disease and the discovery of neurofilament light protein as a susceptibility/risk biomarker that predicts phenoconversion, has ushered in a new era of trials that aim to prevent clinically manifest SOD1 ALS. The 30-year journey from gene discovery to gene therapy has not only uncovered the pathophysiology of SOD1 ALS, but has also facilitated the development of biomarkers that should aid therapy development for all forms of ALS.
18Long-term treatment of SOD1 ALS with tofersen: a multicentre experience in 17 patients.PubMed
Mario Sabatelli, Federica Cerri, Riccardo Zuccarino, et al.
J Neurol. 2024 Aug;271(8):5177-5186. doi: 10.1007/s00415-024-12437-7. Epub 2024 Jun 3.
BACKGROUND: In Amyotrophic Lateral Sclerosis (ALS) patients with SOD1 mutation the intrathecal administration of tofersen slowed down the progression of disease in a controlled clinical study, but results were not statistically significant. METHODS: In this multicentre, observational study, we evaluated a cohort of 27 ALS-SOD1 patients who were treated with tofersen, focussing on 17 patients who were followed for at least 48 weeks (median period of 84 weeks, range 48-108). We compared the clinical slopes, as measured by ALSFRS-R, MRC scale and Forced Vital Capacity, during tofersen treatment with retrospective data at 1 year prior to therapy. Cerebrospinal fluid (CSF) and serum neurofilament light chains (NFL) were measured in all patients. RESULTS: Cumulative evaluation of the ALSFRS-R and MRC progression rates showed a statistically significant change during treatment with respect to the period prior to therapy (p = 0.023 and p = 0.007, respectively). The analysis of individual patients showed that nine of the seventeen patients substantially stabilized or slightly improved. Four patients deteriorated during treatment, while in the remaining patients the very slow course did not allow to identify significant changes. CSF and serum NFL concentration markedly decreased in the near totality of patients. Increased levels of white blood cells and proteins in the CSF were found in 60% of patients. Such alterations were clinically asymptomatic in all but two patients who showed an acute pure motor radiculitis, which responded to steroid therapy. CONCLUSIONS: Clinical findings and NFL analysis strongly suggest that tofersen may have a disease-modifying effect in a subset of SOD1-ALS patients.
19ALSUntangled #71: Nuedexta.PubMed
Yuyao Sun, Michael Benatar, Javier Mascías Cadavid, et al.
Amyotroph Lateral Scler Frontotemporal Degener. 2024 Feb;25(1-2):218-222. doi: 10.1080/21678421.2023.2239292. Epub 2023 Jul 26.
Nuedexta is a combination of dextromethorphan hydrobromide and quinidine sulfate and was approved by the Food and Drug Administration (FDA) in 2010 to treat pseudobulbar affect (PBA). There have since been anecdotal case reports of bulbar function improvements after Nuedexta treatment. Here, we review the off-label use of Nuedexta for improving bulbar function in people with ALS. Nuedexta has plausible mechanisms for protecting brain stem motor neurons via its effects on S1R and glutamate excitotoxicity. Recent clinical trials support that Nuedexta can improve bulbar function in PALS, with or without PBA. Nuedexta causes mild to moderate side effects. Based on this information, we support considering Nuedexta treatment for bulbar dysfunction in ALS patients with or without PBA.
20Genetic Myelopathies.PubMed
Kara Stavros
Continuum (Minneap Minn). 2024 Feb 1;30(1):119-132. doi: 10.1212/CON.0000000000001377.
OBJECTIVE: This article provides an overview of genetic myelopathies, a diverse group of inherited, degenerative conditions that may be broadly categorized as motor neuron disorders, disorders of spinocerebellar degeneration, leukodystrophies, and hereditary spastic paraplegia. Clinical examples from each category are provided to illustrate the spectrum of genetic myelopathies and their distinguishing features that aid in differentiating genetic myelopathies from potentially treatable acquired causes of myelopathy. LATEST DEVELOPMENTS: Advances in genetic testing have vastly enhanced current knowledge of genetic myelopathies and the ability to diagnose and provide appropriate counseling to patients and their families. However, potential health care disparities in access to genetic testing is a topic that must be further explored. Although treatment for most of these conditions is typically supportive, there have been recent therapeutic breakthroughs in treatments for amyotrophic lateral sclerosis, spinal muscular atrophy, and Friedreich ataxia. ESSENTIAL POINTS: Genetic myelopathies may present with chronic and progressive symptoms, a family history of similar symptoms, and involvement of other structures outside of the spinal cord. Imaging often shows spinal cord atrophy, but cord signal change is rare. Exclusion of reversible causes of myelopathy is a key step in the diagnosis. There are many different causes of genetic myelopathies, and in some cases, symptoms may overlap, which underscores the utility of genetic testing in confirming the precise underlying neurologic condition.