Amyotrophic lateral sclerosis (ALS) was first described by Jean-Martin Charcot in 1869 as an inexorably progressive disease primarily associated with degeneration of upper and lower motor neurons [1]. The early 1990s was an important turning point in the study of ALS when the positive results of a large therapeutic trial of riluzole, an anti-glutamatergic agent, were published, showing a prolongation of patient survival [2]. As a result, riluzole was approved by the FDA as the first drug for ALS. To date, it is the only therapeutic agent approved in both the United States and Europe with a modest effect, prolonging patients’ lives by only a few months without significantly improving functional deterioration [3]. Edaravone (Radicava^TM) was approved by the Food and Drugs Administration (FDA) in 2017 but not by the European Medicines Agency (EMA). Approval was based on a phase III study showing that edaravone slowed the loss of physical function by 33% at 24 weeks compared with placebo on the ALSFRS-R scale [3]. However, the efficacy of the treatment remained controversial due to the short duration of the study and the strict inclusion criteria, which were limited to patients with an early stage of the disease. Only the significant improvement in the symptomatic treatment of ALS had a significant impact on patient survival and quality of life [4]. In particular, the development of non-invasive ventilators and the improvement of bronchial suction techniques have placed the management of ALS in the context of multidisciplinary care [5].

Table 1 provides a non-exhaustive list of ongoing clinical trials to illustrate the variety of different disease mechanisms being investigated in this complex and multifactorial disease. Recently, two drugs have been approved in some countries. The IV formulation of the drug (Radicava^TM) had previously been approved by the FDA in 2017. The approval was based on a phase III study that showed edaravone slowed the loss of physical function by 33% after 24 weeks compared to placebo on the ALSFRS-R scale [3]. However, the effectiveness of the treatment remained controversial, and it was not approved by EMA. One reason for this was the short duration of the trial and the strict inclusion criteria, which were limited to patients in the early stage of the disease. The high level of care required with repeated daily IV infusions was a limitation for prescribing the drug. This led to the development of an oral form of edaravone (Radicava ORS^TM) by Mitsubishi Tanabe Pharma, which was recently approved by the FDA in May 2022, and a phase III trial is currently underway to assess the long-term safety and tolerability of oral edaravone over 96 weeks (NCT04577404). The second drug is from Amylyx Pharmaceuticals, an oral, fixed-dose co-formulation of sodium phenylbutyrate and ursodoxicoltaurine (Albrioza^TM) to address both mitochondrial dysfunction and endoplasmic reticulum stress. In June 2022, the co-formulation received its first conditional approval in Canada for the treatment of (ALS) in adults. The approval was based on the results of the multicentre phase II CENTAUR trial (NCT03127514), in which the slowing of progression of ALS with the treatment compared with placebo [20].

Another therapeutic approach that has recently gained renewed interest is the targeting of muscle abnormalities in ALS [68]. The first rationale is neuroprotective, as changes in the muscle and neuromuscular junction may play a role in retrograde degeneration, as suggested by our recent work on the role of secretion of toxic exosomes by muscle in motor neuron degeneration [67]. A second approach is symptomatic by increasing muscle contractility, with two troponin activators in development, tirasemtiv [24,25] and reldesemtiv (NCT04944784), or improving muscle mass and strength [69].

Recently, experimental strategies targeting genes have come to the forefront of clinical research, offering the promising therapeutic potential for ALS and hope for patients with ALS. Several technologies are being tested in preclinical or clinical phases. These include antisense oligonucleotides (ASO), interfering RNAs, viral vectors, or gene editing with CRISPR/Cas9 [70]. Successful treatment with an ASO (Nusinersen^TM) and then with a viral vector (Zolgensma^TM) for another motor neuron disease, spinal muscular atrophy (SMA), has raised hopes that these approaches will lead to approved drugs for ALS in the short term. It should be emphasized, however, that in autosomal dominant forms of ALS, it is no longer a question of compensating for the loss of function of a deleterious gene, as is the case with SMA, but on the contrary of decreasing the expression of a mutation that leads to a toxic gain of function. Such approaches are currently being tested in clinical trials for patients with mutations in SOD1, C9ORF72, and FUS genes.

The most advanced ASO-based treatment is Tofersen^TM, developed by Biogen, which is designed to reduce the synthesis of the SOD1 protein [35,71]. The VALOR study enrolled 108 ALS patients with an SOD1 mutation who were treated for 28 weeks (NCT02623699). The main results were disappointing, as the main objective of slowing functional deterioration as measured by the ALSFRS-R was not achieved [71]. However, Tofersen^TM will apply for approval under the accelerated approval process based on data showing a marked decrease in neurofilament light (NfL) levels, a biomarker of neuronal degeneration, and a reduction in SOD1 protein associated with a trend towards less disease progression [71]. Based on the reasonable assumption that treatment is more effective at an early stage of degeneration, a clinical trial has recently been started in subjects who are carriers of the SOD1 mutation and do not yet have clinical manifestations of the disease (ATLAS study, NCT04856982). The study is investigating whether Tofersen^TM can delay the onset of the disease [72,73]. Subjects are eligible for intervention in this study if the follow-up of the subjects reveals an increase in NfL levels in the blood above a certain threshold that has been shown to predict the onset of symptoms within one to two years [73,74].

A study has been conducted with another ASO-based treatment, Tadnersen^TM (BIIB078), which selectively inhibits the mutant C9ORF72 transcripts [75,76]. Although the therapy was generally safe and well tolerated in people with C9ORF72-associated ALS, it did not result in significant clinical benefit compared with placebo. The extension study was stopped, and clinical development was discontinued. Wave Life Sciences is taking a similar approach with its investigational drug WVE-004, a stereopure ASO, targeting variants containing G4C2, a hexanucleotide repeat expansion associated with the C9ORF72 gene. This study, the phase Ib/IIa FOCUS -C9 trial (NCT04931862), was initiated in August 2021 and is evaluating WVE-004 in C9ORF72-associated ALS and frontotemporal dementia. A phase III trial of Jacifusen^TM (NCT04768972), an ASO designed to reduce FUS protein synthesis from FUS mRNA, is ongoing for patients with FUS gene mutations associated with aggressive juvenile forms of ALS [77,78]. In contrast to ASOs targeting inherited forms of ALS, other strategies are currently being developed that are applicable to sporadic cases and aim to modulate the expression of disease-modifying genes. A phase I trial of BIIB105, an ASO targeting the ataxin-2 gene, is currently underway in sporadic patients with ALS (NCT04494256) [79]. The first rationale is that polyglutamine expansions in ataxin-2 increase the risk of ALS in people who carry them. Secondly, work in yeast and fly models has shown that ataxin-2 promotes aggregation and toxicity of the TDP-43 protein [80].

However, recent evidence has raised awareness that while these strategies will certainly diversify, the challenge of effectiveness and safety remains significant. These risks should be considered and are clearly underscored by the failure of a trial of the ASO Tominersen^TM in Huntington’s disease, where the trial was stopped prematurely because the participants’ symptoms worsened [81]. A major concern with ASO treatment is that the treatment that aims to decrease the levels of the abnormal protein also affects its normal counterpart and, therefore, its physiological function. Among ALS causal mutation, this concern is important with C9ORF72 mutations; whether the mechanism is loss and/or gain of function remain controversial [82]. Strategies based on genome editing, in particular CRISPR/Cas9 technology, could specifically target the genetic mutations, such as removing the intronic position of the C9ORF72 repeat expansion by a ‘cutting-deletion-fusion’ method [11,83,84]. A second risk is the potential immunogenicity of ASO and the risk of meningitis when administered intrathecally. Serious neurological events were reported in 4.8% of ALS patients receiving Tofersen^TM, including two cases of myelitis (2.0%).

The therapeutic approach using stem cells has recently been promoted as a potential neuroprotective therapeutic strategy for ALS. In particular, mesenchymal stem cells (MSCs) have multiple effects, such as stimulation of intrinsic neurogenesis, the release of various neurotrophic factors, and modulation of immune-inflammatory processes, transforming the patient’s environment from a pro-inflammatory toxic state to an anti-inflammatory and neuroprotective state [85]. Several studies investigating the effect of therapeutic approaches using MSCs in mouse disease models have shown that motor neuron loss was slower in the group treated with MSCs [86,87,88,89,90,91]. Subsequently, several clinical trials were conducted to investigate the therapeutic effect of MSCs in ALS patients using intrathecal or intraspinal administration of bone marrow-derived mesenchymal or mononuclear cells or fetal neural stem cells [92,93,94,95]. However, a recent phase III trial of intrathecal administration of MSCs in ALS patients did not meet its primary endpoint of a change in ALS decline, although participants with less severe disease retained more function compared with the placebo group (NCT03280056) [96]. It shows that there is still much to be done in terms of the source of stem cells, the mode of administration, the selection of potentially better-responding patients, clinical endpoints, and safety [97,98,99,100,101,102].