Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disorder, characterized by progressive and selective degeneration of upper motor neurons situated in the motor cortex, and lower motor neurons localized in the brainstem and spinal cord (Hardiman et al., 2017, Robberecht and Philips, 2013). In general, the disease is fast progressing starting with muscle weakness and eventually leading to paralysis and respiratory failure, with death as an unavoidable consequence on average within 2–5 years after symptom onset. Although motor dysfunction is a major sign of ALS, almost 50% of the patients also exhibit subtle extra-motor symptoms, such as cognitive and/or behavioural impairment. Moreover frontotemporal dementia (FTD) can be a comorbidity of ALS, pointing to a continuum between these diseases (ALS/FTD) (Swinnen & Robberecht, 2014).

In 10% of ALS cases, the disease runs in the family (familial ALS, fALS), while in the remaining 90%, no apparent family history can be observed (sporadic ALS, sALS). In the past decade, genetic studies have identified many ALS-associated genes, both in familial and sporadic cases, with the superoxide dismutase 1 (SOD1), fused in sarcoma (FUS), TAR DNA binding protein (TARDBP) and chromosome 9 open reading frame 72 (C9orf72), as the most frequent ones (Al-Chalabi et al., 2017, Taylor et al., 2016). However, most ALS cases remain of unknown cause.

Since the disease was first described by Charcot in 1869, our knowledge about ALS has increased enormously. Major advances have been made in elucidating the genetic causes and understanding the underlying pathogenic mechanisms (Mead, Shan, Reiser, Marshall, & Shaw, 2023). However, translating this knowledge into therapeutic strategies for patients has proven to be a challenge as is demonstrated by the lack of an effective treatment or cure for ALS. Indeed, the clinical trials have been plagued by high failure rate (Petrov, Mansfield, Moussy, & Hermine, 2017). So far, four disease-modifying therapies [riluzole (Wagner & Landis, 1997), edaravone (Safety & efficacy, 2017), AMX0035 (Sun, Li, & Bedlack, 2023) and tofersen (Miller et al., 2022)] are approved by the U.S. Food and Drug Administration (FDA), of which two (riluzole and tofersen) are accepted by the European Medicines Agency (EMA). Some of these therapies are only suitable for a small group of patients, such as tofersen, which is only beneficial for patients with SOD1 mutations (∼1–2% of all ALS patients). The other therapies can be used for a wider group of ALS patients, but are unable to reverse or halt the disease. Although many more compounds have been tested in clinical trials, demonstrating effectiveness has been a major hurdle in obtaining approval for use in the clinic. Several aspects may contribute to or cause this unsatisfactory result.

First, ALS is a highly heterogenous disorder that leads to a diverse group of patients, both genetically and clinically (Masrori & Van Damme, 2020). As a result, patients with a different genetic background may respond differently to certain therapeutic agents. Also clinically, some patients present with a much faster progressing disease than others, and in order to avoid introducing bias, it would be beneficial to include stratification based on parameters, such as genetics (Eijk et al., 2017), disease stage (Balendra et al., 2015) and progression rate (Berry et al., 2018).

Second, demonstrating effectiveness of a compound in a measurable way has been a major hurdle in obtaining approval of a compound for use in the clinic. In this context, the use of biomarkers that can monitor disease progression, prognosis and therapeutic efficacy are extremely informative, but have been lacking for ALS clinical trials. Recent advances in this field have prompted the use of neurofilaments as a biomarker for axonal degeneration in ALS (Poesen and Van Damme, 2019, Poesen et al., 2017, Witzel et al., 2022). Neurofilament light (NFL) levels appear to be a readout for ALS progression and severity, which renders measuring baseline NFL levels a useful approach for stratifying patients. In the trial that led to the approval of tofersen, this stratification method was applied and lowering of NFL correlated with clinical improvement (Meyer et al., 2023, Miller et al., 2022). These findings highlight the added value of including reliable biomarkers in the assessment of novel drug candidates.

Third, the scarcity of representative models with a high predictive power may have also hampered development of effective therapeutic strategies. Although several promising treatment options were discovered in animals, these failed to develop into a targeted and effective therapy for ALS patients. Improving the current pre-clinical model approaches may therefore aid in successful therapeutic translation. Here, we review major advances that have been made in this field and we elaborate on developments which hold promise to facilitate transforming scientific knowledge into clinical benefit.