• What is amyotrophic lateral sclerosis (ALS)

    ALS is the third most common neurodegenerative disease after Alzheimer’s and Parkinson’s diseases. The worldwide ALS prevalence is 4.42 per 1,00,000 people. (Xu et al., 2020) The onset of the disease is most common in people in their 40s to 70s, and 90% of cases occur without any family history of the disease. However, approximately 10% of these cases are familial ALS.

    Once the disease develops, the patient gradually becomes immobile, has difficulty eating and speaking, and is unable to breathe. A ventilator can sustain life, but paralysis progresses throughout the body. The average life expectancy with a ventilator is 7 years. (Hayashi et al., 2020)

    Unfortunately, there is no curative therapy; however, there are drugs that can delay the time to ventilator use by a few months. Only the motor nerves are affected (degenerated), and patients gradually lose the ability to move their bodies while remaining conscious. The disease is also characterized by a very heavy burden of nursing care, as the patient requires around-the-clock care.

    There are several ongoing studies worldwide to achieve a fundamental cure.

    This website provides the latest information on ALS clinical trials, based on scientific evidence.

    Daisuke Ito M.D. Ph.D.
    Specially Appointed Professor
    Department of Physiology/Memory center
    Keio University School of Medicine
    35 Shinanomachi, Shinjuku-ku,
    Tokyo 160-8582, Japan



    Kensuke Okada

    #The following are the criteria for clinical trials to be considered:

    1) There is a reliable preclinical study

    2) Phase II or higher in principle

    3) High social and medical importance Last update June 17, 2022

  • My contributions in this area (ALS and motor neuron diseases)

    Selected papers (First Author or corresponding Author only; *corresponding Author)
    1)    Ito D*, Suzuki N. Molecular pathogenesis of seipin/BSCL2-related motor neuron diseases. Ann Neurol. 2007; 61(3):237-250.
    Mutant seipin in motor neuron disease seipinopathy has impaired glycosylation due to amino acid substitutions at the glycosylation site. It accumulated in the endoplasmic reticulum, induced endoplasmic reticulum stress, and even cell death.
    2)    Ito D*, Suzuki N. Seipinopathy: a novel endoplasmic reticulum stress-associated disease. Brain. 2008; 132(1):8-15.
    A study outlining the role of endoplasmic reticulum stress in the pathogenesis of seipin/BSCL2-related diseases proposed a new disease concept of seipinopathy.
    3)    Ito D*, Seki M, Tsunoda Y, Uchiyama H, Suzuki N. Nuclear transport impairment of ALS-linked mutations in FUS/TLS. Ann Neurol. 2011; 69(1):152-162.
    Mutations in the familial ALS-causing gene, FUS accumulate in the C-terminal nuclear localization signal and cause abnormal localization in the cytoplasm. The FUS mutation induces abnormal formation of stress granules as well as TDP-43, a major ALS accumulation protein. Therefore, TDP-43, an RNA-binding protein, and FUS form a common pathway that induces neurodegeneration in ALS patients. (Award from the Japanese Dementia Society)
    4)    Nihei Y, Ito D*, Suzuki N. Roles of ataxin-2 in pathological cascades mediated by TAR DNA-binding Protein 43 (TDP-43) and Fused in Sarcoma (FUS). J Biol Chem. 2012; 287: 41310–41323.
    To better understand the molecular mechanisms of ALS/FTLD-U, we investigated the associations among ataxin 2 and TDP-43 to clarify how ataxin 2 modifies the pathological pathways involving TDP-43. Endogenous ataxin 2 is recruited to cytoplasmic inclusion bodies (mRNP granules). Altered ataxin 2 levels impair the formation of mRNP granules and enhance the excessive cytoplasmic expression of TDP-43 possibly leading to enhanced RNA dysregulation.

    5)    Yamakawa M, Ito D*, Honda T, Kubo K, Noda M, Nakajima K, Suzuki N. Characterization of the dipeptide repeat protein in the molecular pathogenesis of c9FTD/ALS. Hum Mol Genet. 2015; 24(6):1630-1645.
    This study provides novel evidence that (1) poly-GA, GR, and PR have a strong tendency of inclusion body (IB) formation in vitro and in vivo, (2) three DRPs, poly-GA, GP, and GR, induce ubiquitin–proteasome system (UPS) dysfunction, and (3) DRPs potentially affect the level and distribution of TDP-43.

    6)    Shiihashi G, Ito D*, Yagi T, Nihei Y, Ebine T, Suzuki N. Mislocated FUS is sufficient for gain-of-toxic-function amyotrophic lateral sclerosis phenotypes in mice. Brain. 2016; 139(9):2380-2394.
    We generated a mouse model of ALS mutation, FUS nuclear localization signal-deficient FUS, and confirmed motor neurodegeneration. We observed inclusion body formation, a pathological feature of ALS, in these mice, indicating that the gain of toxicity by the mutant FUS in itself is a sufficient condition for the ALS phenotype.
    7)    Ito D*, Hatano M, Suzuki N. RNA-binding proteins and the pathological cascade in ALS/FTD neurodegeneration. Sci Transl Med. 2017; 9(415).
    We described the molecular pathogenesis of ALS; the major ALS-causing proteins share four common biochemical and cellular features. These ALS-related molecules possibly interact to create a pathway for ALS pathogenesis. This review outlines prospects for future ALS research and treatment strategies. (Serika Foundation Award)
    8)    Shiihashia G, Ito D*, Arai I, Kobayashi Y, Hayashi K, Otsuka S, Nakajima K, Yuzaki M, Itohara S, Suzuki N. Dendritic homeostasis disruption in a novel frontotemporal dementia mouse model expressing cytoplasmic fused in sarcoma. EBioMedicine. 2017; 24: 102–115.
    This study aimed to evaluate frontotemporal dementia (FTD) phenotypes and pathophysiology in a novel ALS mouse model expressing FUS with a deleted nuclear localization signal. We believe that our study makes a significant contribution to the literature because it suggests that cytoplasmic FUS aggregates trap messenger ribonucleic acid (mRNA) and its transporters, impairing dendritic mRNA trafficking and translation, which in turn leads to the disruption of dendritic homeostasis and the development of FTD phenotypes.

    9)    Kato C, Morimoto S, Takahashi S, Daté Y, Okada K, Okano H, Nakahara J, Ito D*. J Neurol. 2022;269(5):2634-2640.

    This study aimed to examine whether participation in the clinical trials for amyotrophic lateral sclerosis (ALS) had an influence on the decision-making processes. Participation in a clinical trial decreased willingness to prolong life after the clinical trial. The present results are meaningful for designing clinical trials and discussing life-sustaining treatments for patients with ALS.

    10) Ito D*. Promise of nucleic acid therapeutics for amyotrophic lateral sclerosis. Ann Neurol. Ann Neurol. 2022;91:13-20
    This review provides an overview of current nucleic acid therapeutics, with a focus on ASOs that are being developed for the treatment of ALS, including those directed at superoxide dismutase 1, TDP-43, ataxin-2 (a regulator of TDP-43), stathmin-2 (a protein downstream of TDP-43), C9orf72, and FUS/TLS.

    11) Ito D*, Morimoto S, Takahashi S, Okada K, Nakahara J, Okano H. Maiden voyage: induced pluripotent stem cell-based drug screening for amyotrophic lateral sclerosis. Brain. 2022 doi: 10.1093/brain/awac306.

    This review outlines current progress and potential in drug development against amyotrophic lateral sclerosis (ALS) using induced pluripotent stem cells (iPSCs). We believe that our study makes a significant contribution to the literature because it shows that the accelerating rate of progress in iPSC-based drug discovery in neurodegenerative diseases opens up new avenues for therapy in intractable diseases, including ALS.

  • Glossary*

    1) ALSFRS-R: The revised ALS Functional Rating Scale

    A scale to evaluate the daily life of patients with ALS. This is the most important scale in clinical trials.

    It consists of 12 items (on a 5-point scale from 0 to 4), including speaking, swallowing, personal activities, and walking, and the total score [0 (most severe) to 48 (normal)] was used to evaluate the effectiveness of the treatment.

    A difference of 20% or more is considered significant for the treatment efficacy (Castrillo-Viguera et al., 2010).

    2) NPPV (Noninvasive Positive Pressure Ventilation)

    Methods of ventilatory management for patients with poor respiratory condition. Ventilation was performed using a mask without tracheotomy.

    3) (Japan) ALS Severity Classification

    Severity 1: Patient can generally perform household chores and do work.

    Severity 2: Housework and employment are difficult but the patient is generally independent in daily living (personal care).

    Severity 3: The patient is unable to eat, urinate, or move around on his/her own, and requires assistance in daily living.

    Severity 4: Patient has difficulty breathing, feeding, or swallowing.

    Severity 5: Tracheostomy, parenteral nutrition (tube feeding, central venous nutrition, etc.), use of ventilator.

    4) SOD1 gene

    The second most common familial ALS causative gene accounts for 23% of all ALS cases. The location of the mutation in the gene can predict the rate of progression of symptoms to some extent. Rapidly progressive forms of ALS develop respiratory failure within 2–3 years of onset (e.g., A5V mutation). The non-rapidly progressive form is more gradual and may take up to 10 years after onset to reach the point of difficulty in walking. (e.g., the H46R mutation)

    5) Endoplasmic reticulum stress

    A phenomenon caused by accumulating unfolded protein (denatured) in the endoplasmic reticulum. Endoplasmic reticulum stress induces changes in protein expression and cell signaling mechanisms and misfolded protein degradation as a defense response.

    6) C9orf72 gene

    Hexanucleotide repeat in the C9orf72 gene is the most common causative mutation of familial ALS.


    7) Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database https://ncri1.partners.org/ProACT

    This database contains data from 11,000 patients, who participated in 23 Phase II and III clinical trials. Researchers can access and use the database free of charge. In particular, data from the placebo treatment group were used as the control group for the open-label trials.

    8) Japanese Consortium for Amyotrophic Lateral Sclerosis Research (JaCALS)

    A Japanese research organization that clarifies the pathogenesis of ALS and the results will lead to the development of future treatments.