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渐冻症可以治愈么？最新研究进展如何
非常遗憾地告诉你，目前的医学手段还无法彻底治愈渐冻症（肌萎缩侧索硬化症，ALS）。这是一种进行性、致命的神经退行性疾病，目前的治疗目标主要是延缓病情发展、控制症状以及提高患者的生存质量 。
虽然“彻底治愈”尚不可得，但请不要灰心，近年来对抗这种疾病的“武器库”已经大大扩充。特别是基因治疗和早期生物标志物的研究取得了突破性进展，部分类型的渐冻症患者已经迎来了针对病因的精准治疗药物。
以下是关于渐冻症治疗现状及最新科研进展的详细解读。
一、 为什么渐冻症这么难治？（核心困境）
要理解为什么难治，我们得先知道身体里发生了什么。
1. 身体的“电线”断了 我们的大脑像是一个总指挥部，肌肉是执行命令的士兵，而运动神经元就是连接二者的“电话线”。渐冻症就是这些“电话线”莫名其妙地枯萎、断裂了。因为收不到命令，肌肉就会以为自己没用了，逐渐萎缩、无力，最终导致患者像被“冻住”一样瘫痪。最致命的是，这种“断线”会波及呼吸肌，导致大多数患者在确诊后平均 2-5 年内因呼吸衰竭离世 。
2. 找不到唯一的“凶手” 渐冻症最棘手的地方在于它的成因非常复杂。
- 遗传因素： 只有约 10% 的病例是家族遗传的（家族性 ALS），这通常与特定的基因突变有关，比如 C9orf72（最常见）、SOD1、FUS 和 TARDBP 等基因 。
- 散发病例： 剩下的 90% 都是散发病例，家里没人得过这病。科学家推测这可能是基因易感性加上环境因素（如毒素、病毒、氧化应激等）共同作用的结果，但这背后的具体机制像是一个黑盒子，至今没有完全解开 。
因为找不到单一的病因，研发一种通用的“解药”就变得异常困难。
二、 现有的“盾牌”：我们如何对抗它？
虽然没有“治愈”的魔法药水，但医生手里有几块“盾牌”可以帮患者抵挡病魔的攻势。
1. 药物治疗：踩下刹车 目前主要有几种药物被批准用于治疗 ALS，它们的作用不是修好“电话线”，而是试图减慢“电话线”断裂的速度：
- 利鲁唑 (Riluzole)： 这是最早的药物，它可以保护神经元免受一种叫“谷氨酸”的化学物质的过度刺激（就像防止电线过热烧断）。它能适度延长生存期 。
- 依达拉奉 (Edaravone)：这是一种抗氧化剂，你可以把它想象成“除锈剂”，帮神经细胞清除有害的氧化物质，延缓功能丧失 。
- 苯丁酸钠/牛磺熊去氧胆酸 (AMX0035)： 这是一种较新的组合药物，旨在保护细胞内的能量工厂（线粒体）和蛋白质加工厂（内质网），已被证实能延缓病情进展 。
2. 多学科护理：全方位的生命支持 研究发现，一个由神经科医生、营养师、呼吸科医生等组成的“多学科专家团队”来照顾患者，其效果甚至比单吃药更好。
- 呼吸支持： 当呼吸肌无力时，使用无创呼吸机（像个面罩一样戴着）可以显著延长生存期并改善睡眠质量 。如果患者选择气管切开术（有创通气），生存期可以延长平均 2 年以上 。
- 营养支持： 很多患者因为吞咽肌肉无力，吃不下饭。通过胃造瘘术（PEG，在肚子上留个小口直接喂食），可以保证营养，维持体重，这对对抗疾病至关重要 。
三、 最新的“利剑”：前沿研究进展
这是最让人感到希望的部分。科学界正在从“盲目尝试”转向“精准打击”。
1. 基因治疗的历史性突破：Tofersen
这是近年来最大的好消息。2023年，美国 FDA 批准了一种名为 Tofersen (商品名 Qalsody) 的新药 。
- 原理： 这是一种反义寡核苷酸 (ASO) 药物。听起来很拗口，你可以把它想象成一条“特殊的胶带”。有些患者得病是因为 SOD1 基因写错了代码，产生了一种有毒的蛋白质。Tofersen 就像胶带一样，贴在这个错误的基因信使上，让它闭嘴，不再产生毒蛋白 。
- 效果： 临床试验显示，它能显著降低患者体内的神经损伤标志物，并在长期使用中稳定肌力。这是人类历史上第一款针对 ALS 特定基因成因的疗法 。
- 局限： 它只适用于携带 SOD1 基因突变的患者（约占所有 ALS 患者的 2%）。虽然受众少，但这证明了“基因修正”这条路是走得通的。
2. 捕捉“火灾前的烟雾”：神经丝轻链 (NfL)
过去，医生判断药有没有效，得等几个月看患者是不是瘫痪得更厉害了。现在，科学家找到了一种极为重要的生物标志物——神经丝轻链 (NfL) 。
- 什么是 NfL？ 当神经细胞（电话线）受损断裂时，里面的结构蛋白（NfL）就会漏到血液和脑脊液里。这就像大楼着火前冒出的烟雾。
- 作用： 血液里的 NfL 浓度越高，说明神经破坏越严重。现在，医生可以通过验血检测 NfL 来快速判断病情发展速度，或者判断新药是不是起效了（如果药有效，NfL 水平应该下降）。这大大加速了新药研发的进程。
3. 扼杀在摇篮里：ATLAS 研究
基于 Tofersen 和 NfL 的发现，科学家正在进行一项名为 ATLAS 的大胆试验 。
- 思路： 对于那些携带致病基因但还没发病的人，我们能不能在他们感到无力之前就动手？
- 做法： 监测这些携带者的血液 NfL 水平。一旦发现 NfL 升高（说明神经开始受损，尽管此时人可能还没感觉），立刻使用 Tofersen 进行干预。
- 意义： 如果成功，这将是 ALS 治疗史上第一次实现“预防性治疗”，可能将发病时间推迟数年甚至更久 。
4. 探索更多靶点：不仅是基因
除了基因，科学家还在研究其他机制：
- 修复能量工厂： 有研究（如药物 R13）试图激活特定的信号通路（TrkB），帮助神经细胞内的线粒体（电池）恢复功能，在小鼠实验中成功改善了运动能力 。
- 处理垃圾蛋白： 绝大多数 ALS 患者（97%）的神经细胞里都有一种叫 TDP-43 的蛋白质异常堆积 。科学家正在寻找能清除这些“垃圾堆”或者防止它们乱跑的方法 。
- 干细胞疗法： 虽然目前某些干细胞疗法（如间充质干细胞）的 III 期临床试验未能达到预期疗效 ，但科学界仍在探索利用干细胞分泌的神经营养因子来保护残留神经元的可能性。
四、 总结
虽然渐冻症目前不可治愈，且病情通常会持续进展 ，但我们正处于一个认知的转折点：
- 从“绝症”到“慢性病”的努力： 现有的药物配合呼吸和营养支持，已经能让患者活得更长、更有尊严 。
- 精准医疗的曙光： SOD1 基因药物 Tofersen 的上市证明了针对病因治疗是可行的，未来针对其他更常见基因（如 C9orf72）的疗法也在路上了 。
- 早期干预的希望： 血液标志物 NfL 的应用，让我们能在症状出现前或早期就察觉病情变化，为未来的“治未病”打下基础 。
对于患者和家属而言，积极配合多学科治疗、保持营养状态、根据医生建议参与合适的临床试验，是目前最科学的应对方式。
References
1Amyotrophic lateral sclerosis: a clinical review.PubMed
P Masrori, P Van Damme
Eur J Neurol. 2020 Oct;27(10):1918-1929. doi: 10.1111/ene.14393. Epub 2020 Jul 7.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder affecting primarily the motor system, but in which extra-motor manifestations are increasingly recognized. The loss of upper and lower motor neurons in the motor cortex, the brain stem nuclei and the anterior horn of the spinal cord gives rise to progressive muscle weakness and wasting. ALS often has a focal onset but subsequently spreads to different body regions, where failure of respiratory muscles typically limits survival to 2-5 years after disease onset. In up to 50% of cases, there are extra-motor manifestations such as changes in behaviour, executive dysfunction and language problems. In 10%-15% of patients, these problems are severe enough to meet the clinical criteria of frontotemporal dementia (FTD). In 10% of ALS patients, the family history suggests an autosomal dominant inheritance pattern. The remaining 90% have no affected family members and are classified as sporadic ALS. The causes of ALS appear to be heterogeneous and are only partially understood. To date, more than 20 genes have been associated with ALS. The most common genetic cause is a hexanucleotide repeat expansion in the C9orf72 gene, responsible for 30%-50% of familial ALS and 7% of sporadic ALS. These expansions are also a frequent cause of frontotemporal dementia, emphasizing the molecular overlap between ALS and FTD. To this day there is no cure or effective treatment for ALS and the cornerstone of treatment remains multidisciplinary care, including nutritional and respiratory support and symptom management. In this review, different aspects of ALS are discussed, including epidemiology, aetiology, pathogenesis, clinical features, differential diagnosis, investigations, treatment and future prospects.
2[Amyotrophic lateral sclerosis (ALS) - diagnosis, course of disease and treatment options].PubMed
Thomas Meyer
Dtsch Med Wochenschr. 2021 Dec;146(24-25):1613-1618. doi: 10.1055/a-1562-7882. Epub 2021 Dec 8.
Amyotrophic lateral sclerosis (ALS) is an adult-onset motor neuron disorder which is characterized by progressive motor symptoms, such as muscle weakness, muscle atrophy and spasticity. In Germany, 6000-8000 people are affected by ALS. Between 1200 and 1600 newly diagnosed patients are expected each year. Protein deposits in the cytoplasm of motor neurons are a molecular feature of ALS. The most common protein aggregates result from excessive deposition of TDP-43. Familial ALS is present in 5 to 10 % of all ALS patients. Common causal genes include C9orf72, SOD1, FUS, and TARDBP. Genetic factors may be involved even without a family history of ALS and may be underestimated. The disease course and progression are highly variable. Symptom severity and rate of progression are determined by the ALS Functional Scale (ALSFRS-R). Beyond clinical symptoms and the patient's perception of disease burden, measurement of slow vital capacity (SVC), peak cough flow (PCF), and body mass index (BMI) are used to underscore the indications for ventilatory and nutritional interventions, as well as palliative care. The validity of the biomarker neurofilament light chain (NF-L) for estimating prognosis is currently being investigated. ALS is not curable - however, various individual treatment options have to be considered for improving survival, symptom control and social participation. The care in specialized ALS centers is recommended to ensure optimal treatment regarding symptomatic medication, assistive devices, nutrition support and ventilation therapy. Optimal care is achieved by interdisciplinary collaboration of general practitioners, specialized physicians, neurologists and ALS experts being integrated in multiprofessional care networks.
3Advances in molecular pathology, diagnosis, and treatment of amyotrophic lateral sclerosis.PubMed
Hristelina Ilieva, Mithila Vullaganti, Justin Kwan
BMJ. 2023 Oct 27;383:e075037. doi: 10.1136/bmj-2023-075037.
Although the past two decades have produced exciting discoveries in the genetics and pathology of amyotrophic lateral sclerosis (ALS), progress in developing an effective therapy remains slow. This review summarizes the critical discoveries and outlines the advances in disease characterization, diagnosis, imaging, and biomarkers, along with the current status of approaches to ALS care and treatment. Additional knowledge of the factors driving disease progression and heterogeneity will hopefully soon transform the care for patients with ALS into an individualized, multi-prong approach able to prevent disease progression sufficiently to allow for a dignified life with limited disability.
4Recent advances in the diagnosis and prognosis of amyotrophic lateral sclerosis.PubMed
Stephen A Goutman, Orla Hardiman, Ammar Al-Chalabi, et al.
Lancet Neurol. 2022 May;21(5):480-493. doi: 10.1016/S1474-4422(21)00465-8. Epub 2022 Mar 22.
The diagnosis of amyotrophic lateral sclerosis can be challenging due to its heterogeneity in clinical presentation and overlap with other neurological disorders. Diagnosis early in the disease course can improve outcomes as timely interventions can slow disease progression. An evolving awareness of disease genotypes and phenotypes and new diagnostic criteria, such as the recent Gold Coast criteria, could expedite diagnosis. Improved prognosis, such as that achieved with the survival model from the European Network for the Cure of ALS, could inform the patient and their family about disease course and improve end-of-life planning. Novel staging and scoring systems can help monitor disease progression and might potentially serve as clinical trial outcomes. Lastly, new tools, such as fluid biomarkers, imaging modalities, and neuromuscular electrophysiological measurements, might increase diagnostic and prognostic accuracy.
5Amyotrophic lateral sclerosis.PubMed
David S Younger, Robert H Brown
Handb Clin Neurol. 2023;196:203-229. doi: 10.1016/B978-0-323-98817-9.00031-4.
The scientific landscape surrounding amyotrophic lateral sclerosis has shifted immensely with a number of well-defined ALS disease-causing genes, each with related phenotypical and cellular motor neuron processes that have come to light. Yet in spite of decades of research and clinical investigation, there is still no etiology for sporadic amyotrophic lateral sclerosis, and treatment options even for those with well-defined familial syndromes are still limited. This chapter provides a comprehensive review of the genetic basis of amyotrophic lateral sclerosis, highlighting factors that contribute to its heritability and phenotypic manifestations, and an overview of past, present, and upcoming therapeutic strategies.
6Biomarkers for amyotrophic lateral sclerosis.PubMed
Simon Witzel, Kristina Mayer, Patrick Oeckl
Curr Opin Neurol. 2022 Oct 1;35(5):699-704. doi: 10.1097/WCO.0000000000001094. Epub 2022 Aug 4.
PURPOSE OF REVIEW: Amyotrophic lateral sclerosis (ALS) is an incurable, devastating neurodegenerative disease. Still, the diagnosis is mainly based on clinical symptoms, and the treatment options are strongly limited. However, the pipeline of potential treatments currently tested in clinical trials is promising. This review will discuss developments in ALS biomarker research and applications within the last 2 years and suggest future directions and needs. RECENT FINDINGS: The diagnostic and prognostic utility of neurofilaments, a general marker for axoneuronal degeneration, has been confirmed by further studies in patients with ALS, and neurofilaments are finding their way into routine diagnostic and clinical trials. Additionally, there have been advancements in developing and implementing disease-specific biomarkers, especially in patients with a genetic variant, such as SOD1 or C9orf72 . Here, biomarkers have already been used as target markers and outcome parameters for novel treatment approaches. In addition, several novel biomarkers have shown encouraging results but should be discussed in the context of their early stage of assay and clinical establishment. SUMMARY: The first biomarkers have found their way into clinical routine in ALS. In light of an increasing pipeline of potential treatments, further progress in discovering and implementing novel and existing biomarkers is crucial.
7Care management in amyotrophic lateral sclerosis.PubMed
M-H Soriani, C Desnuelle
Rev Neurol (Paris). 2017 May;173(5):288-299. doi: 10.1016/j.neurol.2017.03.031. Epub 2017 Apr 29.
Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive and fatal neurodegenerative disease characterized by progressive weakness of voluntary muscles of movement as well as those for swallowing, speech and respiration. In the absence of curative treatment, care can improve quality of life, prolong survival, and support ALS patients and their families, and also help them to anticipate and prepare for the end of life. Multidisciplinary management in tertiary centers is recommended in close collaboration with general practitioners, home carers and a dedicated health network. Patients' follow-up deals mainly with motor impairment and physical disability, adaptation, nutrition and respiratory function. Involvement of palliative care as part of the multidisciplinary team management offers patients the possibility of discussing their end of life issues. This review summarizes the different aspects of ALS care, from delivering the diagnosis to the end of life, and the organization of its management.
8Respiratory Failure in Amyotrophic Lateral Sclerosis.PubMed
Shannon Niedermeyer, Michael Murn, Philip J Choi
Chest. 2019 Feb;155(2):401-408. doi: 10.1016/j.chest.2018.06.035. Epub 2018 Jul 7.
Amyotrophic lateral sclerosis is a progressive neuromuscular disease characterized by both lower motor neuron and upper motor neuron dysfunction. Although clinical presentations can vary, there is no cure for ALS, and the disease is universally terminal, with most patients dying of respiratory complications. Patients die, on average, within 3 to 5 years of diagnosis, unless they choose to undergo tracheostomy, in which case, they may live, on average, 2 additional years. Up to 95% of patients with ALS in the United States choose not to undergo tracheostomy; management of respiratory failure is therefore aimed at both prolonging survival as well as improving quality of life. Standard of care for patients with ALS includes treatment from multidisciplinary teams, but many patients do not have consistent access to a pulmonary physician who regularly sees patients with this disease. The goal of this review was to serve as an overview of respiratory considerations in the management of ALS. This article discusses noninvasive ventilation in the management of respiratory muscle weakness, mechanical insufflation/exsufflation devices for airway clearance, and treatment of aspiration, including timing of placement of a percutaneous endoscopic gastrostomy tube, as well as secretion management. In addition, it is important for physicians to consider end-of-life issues such as advanced directives, hospice referral, and ventilator withdrawal.
9Tofersen: First Approval.PubMed
Hannah A Blair
Drugs. 2023 Jul;83(11):1039-1043. doi: 10.1007/s40265-023-01904-6.
Tofersen (Qalsody) is an antisense oligonucleotide being developed by Biogen for the treatment of amyotrophic lateral sclerosis (ALS). On 25 April 2023, tofersen was approved in the USA for the treatment of ALS in adults who have a mutation in the superoxide dismutase 1 (SOD1) gene. This article summarizes the milestones in the development of tofersen leading to this first approval for ALS.
10The sense of antisense therapies in ALS.PubMed
Sien H Van Daele, Pegah Masrori, Philip Van Damme, et al.
Trends Mol Med. 2024 Mar;30(3):252-262. doi: 10.1016/j.molmed.2023.12.003. Epub 2024 Jan 11.
Treatment of patients with amyotrophic lateral sclerosis (ALS) has entered a new era now that encouraging results about antisense oligonucleotides (ASOs) are becoming available and a first ASO therapy for ALS has been approved by the FDA. Moreover, there is hope not only that ALS can be stopped but also that symptoms can be reversed. Until now, degrading ASOs seemed to be successful mostly for rarer forms of familial ALS. However, the first attempts to correct mis-splicing events in sporadic ALS are underway, as well as a clinical trial examining interference with a genetic modifier. In this review, we discuss the current status of using ASOs in ALS and the possibilities and pitfalls of this therapeutic strategy.
11Amyotrophic Lateral Sclerosis and Other Motor Neuron Diseases.PubMed
Aaron Izenberg
Continuum (Minneap Minn). 2023 Oct 1;29(5):1538-1563. doi: 10.1212/CON.0000000000001345.
OBJECTIVE: This article reviews the clinical spectrum of amyotrophic lateral sclerosis (ALS), its variant presentations, and the approach to diagnosis and management. This review includes a detailed discussion of current and emerging disease-modifying therapies and the management of respiratory and bulbar manifestations of disease. An updated review of ALS genetics and pathophysiology is also provided. This article also touches on several other important motor neuron diseases. LATEST DEVELOPMENTS: A new set of simplified diagnostic criteria may help identify patients at earlier stages of the disease. A coformulation of sodium phenylbutyrate and tauroursodeoxycholic acid has been shown to have a significant benefit on disease progression and survival, leading to approval by regulatory authorities in the United States and Canada. An oral formulation of edaravone and an antisense oligonucleotide to a SOD1 gene variation (tofersen) have also recently been approved by the US Food and Drug Administration (FDA). Phase 3 trials of intrathecal mesenchymal stem cells failed to meet primary end points for efficacy. Updated American Academy of Neurology quality measures for the care of patients with ALS were published in 2023. ESSENTIAL POINTS: There has been continued progress in ALS genetics, diagnosis, and disease-modifying therapies. However, we still lack a definitive biomarker or a treatment that can halt the progression or reverse the course of disease. The evolving understanding of the genetic and pathophysiologic underpinnings of disease offers promise for more effective and clinically meaningful treatments in the future.
12Fluid biomarkers for amyotrophic lateral sclerosis: a review.PubMed
Katherine E Irwin, Udit Sheth, Philip C Wong, et al.
Mol Neurodegener. 2024 Jan 24;19(1):9. doi: 10.1186/s13024-023-00685-6.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the loss of upper and lower motor neurons. Presently, three FDA-approved drugs are available to help slow functional decline for patients with ALS, but no cure yet exists. With an average life expectancy of only two to five years after diagnosis, there is a clear need for biomarkers to improve the care of patients with ALS and to expedite ALS treatment development. Here, we provide a review of the efforts made towards identifying diagnostic, prognostic, susceptibility/risk, and response fluid biomarkers with the intent to facilitate a more rapid and accurate ALS diagnosis, to better predict prognosis, to improve clinical trial design, and to inform interpretation of clinical trial results. Over the course of 20 + years, several promising fluid biomarker candidates for ALS have emerged. These will be discussed, as will the exciting new strategies being explored for ALS biomarker discovery and development.
13Amyotrophic Lateral Sclerosis and Other Motor Neuron Diseases.PubMed
Colin Quinn, Lauren Elman
Continuum (Minneap Minn). 2020 Oct;26(5):1323-1347. doi: 10.1212/CON.0000000000000911.
PURPOSE OF REVIEW: This article reviews the clinical features, diagnostic approach, and treatments available for amyotrophic lateral sclerosis (ALS) and other motor neuron diseases. The article also provides an update on the genetics and pathophysiology of ALS. RECENT FINDINGS: ALS remains a clinical diagnosis without a unique biomarker. The areas of greatest progress include a large expansion in the number of genes associated with familial and sporadic ALS. The discovery of these genes, along with other work, has provided a deeper understanding of the mechanisms of motor neuron failure in ALS. Areas of particular interest include the role of transactive response DNA-binding protein 43 and other RNA-processing proteins in the development of disease. SUMMARY: ALS remains a relentlessly progressive disorder with an elusive core pathophysiology. The current mainstay of treatment remains symptom management and palliation, particularly in the setting of a multidisciplinary clinic. The future holds potential for targeted therapies based on an ever-evolving understanding of the pathophysiology of both familial and sporadic ALS.
14Updates 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.
15Clinical 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.
16Current 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.
17[Multidisciplinary care and therapeutic advances in amyotrophic lateral sclerosis].PubMed
José Manuel Matamala, Javier Moreno-Roco, Ignacio Acosta, et al.
Rev Med Chil. 2022 Dec;150(12):1633-1646. doi: 10.4067/s0034-98872022001201633.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that mainly affects the motor system, resulting in progressive weakness and muscle wasting. Despite the tremendous advances in physiopathological and clinical characterization, we do not have a curative treatment yet. The progressive and fatal course of ALS makes its management particularly complex and challenging given the diversity of symptoms presenting during the disease progression. The main goal in the treatment of ALS patients is to minimize morbidity and maximize the quality of life. Currently, a series of therapeutic interventions improve the quality of life and prolong survival, including multidisciplinary care, respiratory management, and disease-modifying therapy. Within the supportive interventions, weight maintenance through nutritional and metabolic support is critical. In addition, the management of neuropsychiatric manifestations and preservation of communicative capacity before speech loss are also crucial. Lastly, early palliative care intervention is essential to optimize symptomatic management. Anticipatory guidelines to face the inevitable patient deterioration should be devised. This article updates the main therapeutic strategies used in these patients, including evolving clinical trials with promising novel therapies.
18Genetic 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.
19Design of a Randomized, Placebo-Controlled, Phase 3 Trial of Tofersen Initiated in Clinically Presymptomatic SOD1 Variant Carriers: the ATLAS Study.PubMed
Michael Benatar, Joanne Wuu, Peter M Andersen, et al.
Neurotherapeutics. 2022 Jul;19(4):1248-1258. doi: 10.1007/s13311-022-01237-4. Epub 2022 May 18.
Despite extensive research, amyotrophic lateral sclerosis (ALS) remains a progressive and invariably fatal neurodegenerative disease. Limited knowledge of the underlying causes of ALS has made it difficult to target upstream biological mechanisms of disease, and therapeutic interventions are usually administered relatively late in the course of disease. Genetic forms of ALS offer a unique opportunity for therapeutic development, as genetic associations may reveal potential insights into disease etiology. Genetic ALS may also be amenable to investigating earlier intervention given the possibility of identifying clinically presymptomatic, at-risk individuals with causative genetic variants. There is increasing evidence for a presymptomatic phase of ALS, with biomarker data from the Pre-Symptomatic Familial ALS (Pre-fALS) study showing that an elevation in blood neurofilament light chain (NfL) precedes phenoconversion to clinically manifest disease. Tofersen is an investigational antisense oligonucleotide designed to reduce synthesis of superoxide dismutase 1 (SOD1) protein through degradation of SOD1 mRNA. Informed by Pre-fALS and the tofersen clinical development program, the ATLAS study (NCT04856982) is designed to evaluate the impact of initiating tofersen in presymptomatic carriers of SOD1 variants associated with high or complete penetrance and rapid disease progression who also have biomarker evidence of disease activity (elevated plasma NfL). The ATLAS study will investigate whether tofersen can delay the emergence of clinically manifest ALS. To our knowledge, ATLAS is the first interventional trial in presymptomatic ALS and has the potential to yield important insights into the design and conduct of presymptomatic trials, identification, and monitoring of at-risk individuals, and future treatment paradigms in ALS.
20R13 preserves motor performance in SOD1 mice by improving mitochondrial function.PubMed
Xiao Li, Chongyang Chen, Xu Zhan, et al.
Theranostics. 2021 May 24;11(15):7294-7307. doi: 10.7150/thno.56070. eCollection 2021.
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by death of motor neurons in the brain and spinal cord. However, so far, there is no effective treatment for ALS. In this study, R13, a prodrug of 7,8-dihydroxyflavone, selectively activating tyrosine kinase receptor B (TrkB) signaling pathway, was administered prophylactically to 40-day old SOD1 mice for 90 days. The motor performance was investigated by rotarod test, climbing-pole test, grip strength test and hanging endurance test. Afterwards, the spinal cord and medulla oblongata of 130-day old mice were harvested, and the proteomics revealed the effect of R13 on mouse protein expression profile. Astrocytes and microglial proliferation were assessed by immunohistochemical analysis. The number of motor neurons in the spinal cord is determined by Nissl staining. The effect of R13 on gastrocnemius morphology was assessed by HE staining. The effect of R13 on the survival rate was accomplished with worms stably expressing G93A SOD1. Behavioral tests showed that R13 significantly attenuated abnormal motor performance of SOD1 mice. R13 reduced the advance of spinal motor neuron pathology and gastrocnemius muscle atrophy. The proliferation of microglia and astrocytes was reduced by R13 treatment. Mitochondriomics analysis revealed that R13 modified the mitochondrial protein expression profiles in the medulla oblongata and spinal cord of SOD1 mice, particularly promoting the expression of proteins related to oxidative phosphorylation (OXPHOS). Further study found that R13 activated AMPK/PGC-1α/Nrf1/Tfam, promoted mitochondrial biogenesis and ameliorated mitochondrial dysfunction. Lastly, R13 prolonged the survival rate of worms stably expressing G93A SOD1. These findings suggest oral R13 treatment slowed the advance of motor system disease in a reliable animal model of ALS, supporting that R13 might be useful for treating ALS.