RARE DISEASE
Motor neuron disease
Motor neuron disease
Motor neuron disease
Synonyms: Anterior horn cell disease
Synonyms: Anterior horn cell disease
Synonyms: Anterior horn cell disease
Drug discovery
1
drug
With orphan designation
Overview
Motor neuron disease (MND) is a fatal, progressive neurodegenerative disorder characterized by degeneration of upper and/or lower motor neurons, leading to muscle weakness, wasting, dysphagia, respiratory compromise, and variable cognitive-behavioral changes [1][3][5]. Also termed amyotrophic lateral sclerosis (ALS) in its most common form, it lacks a cure but benefits from multidisciplinary care to optimize quality of life [1][3][5]. Diagnosis relies on clinical assessment and exclusion of mimics, with riluzole remaining the only disease-modifying therapy with modest survival benefit [5][10].
Population
Incidence: 2.64/100,000 person-years (Netherlands study) [2]; global age-standardized prevalence 3.37/100,000 [6]
Peak onset 50–75 years, with higher prevalence in males (58.4% vs 41.6% in registries) [2][10]
~10% familial inheritance, with genetic mutations (e.g., SOD1) identified in 60% of familial cases [1][5]
Therapies
Pharmacologic: Riluzole (extends survival by 2–3 months), edaravone (slows functional decline), and symptom management for sialorrhea, spasticity, and pain [3][5][10]
Supportive: Non-invasive ventilation, PEG insertion, and multidisciplinary care (nutrition, physiotherapy, speech therapy) [3][9]
Emerging: Terazosin (PGK1 activation in trials) [7], antisense oligonucleotides for SOD1-ALS [10]
Categories: rare neurological diseases
Research Papers
2,528 drug discovery papers about Motor neuron disease, with 8 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2,528 drug discovery papers about Motor neuron disease, with 8 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-08-15 | Update and recommendations on genetic testing for amyotrophic lateral sclerosis in clinical practice: a Brazilian expert view.
Amyotrophic lateral sclerosis (ALS) is a complex and progressive neurodegenerative disorder characterized by the degeneration of both upper and lower motor neurons. Although most ALS cases occur sporadically, without a known family history of the disease, genetic factors play a major role in its pathogenesis through monogenic, oligogenic, or polygenic mechanisms. It is estimated that 10-15% of ALS cases occur in a familial setting; however, a specific monogenic cause cannot always be identified. Establishing the underlying genetic basis in both sporadic and familial ALS is essential, as it enables individualized and family genetic counseling, facilitates the early identification of at-risk or oligosymptomatic relatives, improves the prediction of gene-specific clinical trajectories, and, more recently, determines eligibility for gene-targeted therapies, such as tofersen for SOD1-associated ALS and ulefnersen, currently under clinical investigation, for FUS-associated ALS. Over the years, differing opinions have existed regarding the role of genetic testing in individuals diagnosed with ALS. However, accumulating clinical evidence has increasingly supported the timely and early implementation of genetic testing as part of the standard clinical management of patients with ALS. In this article, we present the perspective of leading Brazilian neurologists specializing in ALS care regarding the current role of genetic testing in clinical practice.
2026-08-06 | The Effectiveness Based on Optimal Dose and Administration Route, and Safety Profiles of Stem Cells and Derived Products in the Treatment of Patients With Amyotrophic Lateral Sclerosis: A Systematic Review and Meta-Analysis.
This systematic review and meta-analysis aimed to evaluate the effectiveness of stem cell therapies for patients with amyotrophic lateral sclerosis (ALS) based on optimal dosing and administration routes, as well as the safety profiles of stem cells and their derived products. The review followed PRISMA guidelines and involved a comprehensive literature search up to October 2025, receiving ethical approval from Tabriz University of Medical Sciences and registration in PROSPERO. It utilized international databases, including PubMed/MEDLINE, Embase, Cochrane Library, Scopus, Web of Science, ProQuest, ClinicalTrials.gov, and Science Direct. The included studies comprised randomized controlled trials (RCTs), quasi-experimental studies, and other interventional designs involving ALS patients treated with stem cell therapies. In total, 31 studies were analyzed, featuring 7 controlled trials with 370 participants and 24 non-controlled pre-post studies with 460 participants. Heterogeneity was evaluated using I 2 statistics, and subgroup analyses were conducted based on treatment duration and dosing. A pooled analysis (treatment group: n = 93; control group: n = 90) demonstrated a significant attenuation in the progression of disease severity, as measured by the ALS Functional Rating Scale (ALSFRS), in stem cell groups versus controls (weighted mean difference [WMD]: 8.89 95% CI: 4.12-13.67; p = 0.0003), which was beneficial for both the ≥10 × 106 and <10 × 106 dose sub-groups. However, a meta-analysis of single-arm studies in two control (pre-intervention) and intervention phases (n = 88) demonstrated no significant difference in progression of ALSFRS between study phases by time: month 3 (WMD: -1.27 (-3.01 to 0.47); p = 0.15), month 6 (WMD: -2.69 (-5.62 to 0.25); p = 0.07), month 9 (WMD: -1.55 (-3.49 to 0.39); p = 0.12), and month 12 (WMD: -7.59 (-13.95 to -1.26); p = 0.02). An accelerated decline in forced vital capacity (FVC) was observed during the intervention phase, with statistically significant reductions at month 3 (WMD: -10.91; 95% CI: -16.39 to -5.43; p < 0.0001) and month 6 (WMD: -15.97; 95% CI: -28.60 to -3.33; p = 0.01) compared with the pre-intervention control phase. Nevertheless, sensitivity analyses excluding studies involving high-dose mesenchymal stem cell (MSC) therapies demonstrated that these differences were no longer statistically significant. Moreover, no significant change in progression rate was observed at month 9 (WMD: -8.10 (-18.25 to 2.06); p = 0.12). The route of MSCs administration (intrathecal [IT], intramuscular [IM], and intravenous [IV]) had no effect on the results of ALSFRS and FVC, reinforced by sensitivity analyses. Adverse events were mostly mild, with headaches most frequent in high-dose groups. Stem cell therapy for ALS appears to be safe, with preliminary evidence suggesting potential therapeutic benefit in slowing disease progression in selected patients. Nevertheless, the existing evidence base remains exploratory, and definitive conclusions regarding clinical effectiveness cannot yet be drawn. Future research should prioritize large-scale and multicenter RCTs with standardized cell manufacturing protocols and longer follow-up periods.
2026-08-04 | Tofersen Treatment in SOD1-ALS: Real-World Evidence from a Retrospective Multicenter Study in France (FORSLA Study).
To evaluate the effectiveness of Tofersen in patients with superoxide dismutase 1 gene (SOD1-ALS) patients in France in a real-world setting, using disease progression within patient comparisons and with a historical cohort. Patients with SOD1-ALS were included from across 19 French FILSLAN network centers. Baseline was defined as the treatment initiation date. Main endpoints were the ALSFRS-R progression rate and plasmatic neurofilament light chain (NfL) levels at baseline and 12 months after baseline. In the Tofersen Cohort (N=46), within-group comparisons showed that the mean ALS functional rating scale revised (ALSFRS-R) progression rate slowed from 0.53 ± 0.5 at baseline to 0.22 ± 0.3 point/month at 12 months (P=.006). NfL levels significantly decreased from 89.0 ± 9.0 pg/ml at baseline to 29.2 ± 19.5.5 at 12 months (P=.004). Exploratory comparisons with a propensity score (PS) matched historical cohort (39 matched pairs) using a mixed-effects model, ALSFRS-R progression rate at baseline, 6 months, and 12 months after baseline, showed no statistically significant differences between groups P=.30, whereas longitudinal ALSFRS-R scores differed significantly between groups (time-treatment interaction P=.006). The mean survival of the PS matched population was longer in the Tofersen Cohort (42.6 months) than the Historical Cohort (31.8 months) P=.004. Time-dependent adjusted cox analysis showed that Tofersen was associated with a reduction in mortality risk (adjusted HR=0.34; 95% CI, 0.12-0.91; P=.03). Tofersen seems to be associated with slower functional decline and reduced NfL levels. While limitations of retrospective design and ALSFRS-R sensitivity must be acknowledged, these findings provide real-world evidence suggesting a clinical benefit of Tofersen.
2026-07-29 | Tofersen treatment in respiratory onset amyotrophic lateral sclerosis and a variant of uncertain significance in SOD1; a case report.
The antisense oligonucleotide tofersen is available for treating amyotrophic lateral sclerosis (ALS) caused by pathogenic SOD1 variants. However, it is unknown whether Variants of Uncertain Significance (VUS) are a viable treatment target. We assessed clinical and biomarker trajectories prior to and after initiation of tofersen in a patient with respiratory onset ALS and a novel c.234_236del p.(Glu79del) VUS in SOD1. After six months of treatment, cerebrospinal fluid (CSF) SOD1 protein decreased by 47%, CSF NfL by 55% and serum NfL by 50%, with trajectories comparable to known pathogenic variants. Functional decline on the ALSFRS-R slowed from 1.52 points per month pre-treatment to 0.52 points per month post-treatment, muscle strength remained stable, and EQ-VAS quality of life scores remained between 60 and 70. The ability to evaluate treatment response on an individual level will help to determine the clinical relevance of VUS as new gene-targeted treatments for ALS become available.
2026-07-16 | Metabolomic analyses of amyotrophic lateral sclerosis, muscle cramps, and TJ-68 treatment.
Most patients with amyotrophic lateral sclerosis (ALS), a fatal motor neuron disease, experience painful muscle cramps. Our recent pilot trial of the Japanese Kampo medicine TJ-68 suggested its efficacy in improving muscle cramps in patients with ALS. This study analyzed plasma metabolomic changes to identify the underlying mechanisms of muscle cramps in ALS and the effects of TJ-68. Plasma was obtained from 11 participants with ALS in the repeated crossover trial at five time points (baseline, two placebo phases, and two TJ-68 phases). Metabolites were analyzed using mass spectrometry. Linear mixed-effects models were applied to identify metabolite changes associated with muscle cramps, determine the effects of TJ-68 on metabolites, and predict which participants would respond to TJ-68. Higher glutamine/glutamate, arginine, and leucine levels were associated with more severe muscle cramps. TJ-68 treatment increased tryptophan and aconitate levels but reduced serotonin and acetylcarnitine levels. Long-chain acylcarnitine levels were correlated with muscle cramp severity, and their levels tended to decrease with treatment. Uric acid, β-aminoisobutyric acid, α-aminoadipic acid, and acetylcholine emerged as predictors of the efficacy of TJ-68. This study identified the metabolite profile of muscle cramps in ALS and the changes in metabolite levels after TJ-68 treatment. Several baseline metabolites were associated with the prediction of the response to muscle cramps following TJ-68 treatment. Uric acid might be particularly useful because of its easy measurement in standard assays. Our study affirms the value of metabolomic technology for future pharmacotherapy and studies in ALS.
2026-08-15 | Update and recommendations on genetic testing for amyotrophic lateral sclerosis in clinical practice: a Brazilian expert view.
Amyotrophic lateral sclerosis (ALS) is a complex and progressive neurodegenerative disorder characterized by the degeneration of both upper and lower motor neurons. Although most ALS cases occur sporadically, without a known family history of the disease, genetic factors play a major role in its pathogenesis through monogenic, oligogenic, or polygenic mechanisms. It is estimated that 10-15% of ALS cases occur in a familial setting; however, a specific monogenic cause cannot always be identified. Establishing the underlying genetic basis in both sporadic and familial ALS is essential, as it enables individualized and family genetic counseling, facilitates the early identification of at-risk or oligosymptomatic relatives, improves the prediction of gene-specific clinical trajectories, and, more recently, determines eligibility for gene-targeted therapies, such as tofersen for SOD1-associated ALS and ulefnersen, currently under clinical investigation, for FUS-associated ALS. Over the years, differing opinions have existed regarding the role of genetic testing in individuals diagnosed with ALS. However, accumulating clinical evidence has increasingly supported the timely and early implementation of genetic testing as part of the standard clinical management of patients with ALS. In this article, we present the perspective of leading Brazilian neurologists specializing in ALS care regarding the current role of genetic testing in clinical practice.
2026-08-06 | The Effectiveness Based on Optimal Dose and Administration Route, and Safety Profiles of Stem Cells and Derived Products in the Treatment of Patients With Amyotrophic Lateral Sclerosis: A Systematic Review and Meta-Analysis.
This systematic review and meta-analysis aimed to evaluate the effectiveness of stem cell therapies for patients with amyotrophic lateral sclerosis (ALS) based on optimal dosing and administration routes, as well as the safety profiles of stem cells and their derived products. The review followed PRISMA guidelines and involved a comprehensive literature search up to October 2025, receiving ethical approval from Tabriz University of Medical Sciences and registration in PROSPERO. It utilized international databases, including PubMed/MEDLINE, Embase, Cochrane Library, Scopus, Web of Science, ProQuest, ClinicalTrials.gov, and Science Direct. The included studies comprised randomized controlled trials (RCTs), quasi-experimental studies, and other interventional designs involving ALS patients treated with stem cell therapies. In total, 31 studies were analyzed, featuring 7 controlled trials with 370 participants and 24 non-controlled pre-post studies with 460 participants. Heterogeneity was evaluated using I 2 statistics, and subgroup analyses were conducted based on treatment duration and dosing. A pooled analysis (treatment group: n = 93; control group: n = 90) demonstrated a significant attenuation in the progression of disease severity, as measured by the ALS Functional Rating Scale (ALSFRS), in stem cell groups versus controls (weighted mean difference [WMD]: 8.89 95% CI: 4.12-13.67; p = 0.0003), which was beneficial for both the ≥10 × 106 and <10 × 106 dose sub-groups. However, a meta-analysis of single-arm studies in two control (pre-intervention) and intervention phases (n = 88) demonstrated no significant difference in progression of ALSFRS between study phases by time: month 3 (WMD: -1.27 (-3.01 to 0.47); p = 0.15), month 6 (WMD: -2.69 (-5.62 to 0.25); p = 0.07), month 9 (WMD: -1.55 (-3.49 to 0.39); p = 0.12), and month 12 (WMD: -7.59 (-13.95 to -1.26); p = 0.02). An accelerated decline in forced vital capacity (FVC) was observed during the intervention phase, with statistically significant reductions at month 3 (WMD: -10.91; 95% CI: -16.39 to -5.43; p < 0.0001) and month 6 (WMD: -15.97; 95% CI: -28.60 to -3.33; p = 0.01) compared with the pre-intervention control phase. Nevertheless, sensitivity analyses excluding studies involving high-dose mesenchymal stem cell (MSC) therapies demonstrated that these differences were no longer statistically significant. Moreover, no significant change in progression rate was observed at month 9 (WMD: -8.10 (-18.25 to 2.06); p = 0.12). The route of MSCs administration (intrathecal [IT], intramuscular [IM], and intravenous [IV]) had no effect on the results of ALSFRS and FVC, reinforced by sensitivity analyses. Adverse events were mostly mild, with headaches most frequent in high-dose groups. Stem cell therapy for ALS appears to be safe, with preliminary evidence suggesting potential therapeutic benefit in slowing disease progression in selected patients. Nevertheless, the existing evidence base remains exploratory, and definitive conclusions regarding clinical effectiveness cannot yet be drawn. Future research should prioritize large-scale and multicenter RCTs with standardized cell manufacturing protocols and longer follow-up periods.
2026-08-04 | Tofersen Treatment in SOD1-ALS: Real-World Evidence from a Retrospective Multicenter Study in France (FORSLA Study).
To evaluate the effectiveness of Tofersen in patients with superoxide dismutase 1 gene (SOD1-ALS) patients in France in a real-world setting, using disease progression within patient comparisons and with a historical cohort. Patients with SOD1-ALS were included from across 19 French FILSLAN network centers. Baseline was defined as the treatment initiation date. Main endpoints were the ALSFRS-R progression rate and plasmatic neurofilament light chain (NfL) levels at baseline and 12 months after baseline. In the Tofersen Cohort (N=46), within-group comparisons showed that the mean ALS functional rating scale revised (ALSFRS-R) progression rate slowed from 0.53 ± 0.5 at baseline to 0.22 ± 0.3 point/month at 12 months (P=.006). NfL levels significantly decreased from 89.0 ± 9.0 pg/ml at baseline to 29.2 ± 19.5.5 at 12 months (P=.004). Exploratory comparisons with a propensity score (PS) matched historical cohort (39 matched pairs) using a mixed-effects model, ALSFRS-R progression rate at baseline, 6 months, and 12 months after baseline, showed no statistically significant differences between groups P=.30, whereas longitudinal ALSFRS-R scores differed significantly between groups (time-treatment interaction P=.006). The mean survival of the PS matched population was longer in the Tofersen Cohort (42.6 months) than the Historical Cohort (31.8 months) P=.004. Time-dependent adjusted cox analysis showed that Tofersen was associated with a reduction in mortality risk (adjusted HR=0.34; 95% CI, 0.12-0.91; P=.03). Tofersen seems to be associated with slower functional decline and reduced NfL levels. While limitations of retrospective design and ALSFRS-R sensitivity must be acknowledged, these findings provide real-world evidence suggesting a clinical benefit of Tofersen.
2026-07-29 | Tofersen treatment in respiratory onset amyotrophic lateral sclerosis and a variant of uncertain significance in SOD1; a case report.
The antisense oligonucleotide tofersen is available for treating amyotrophic lateral sclerosis (ALS) caused by pathogenic SOD1 variants. However, it is unknown whether Variants of Uncertain Significance (VUS) are a viable treatment target. We assessed clinical and biomarker trajectories prior to and after initiation of tofersen in a patient with respiratory onset ALS and a novel c.234_236del p.(Glu79del) VUS in SOD1. After six months of treatment, cerebrospinal fluid (CSF) SOD1 protein decreased by 47%, CSF NfL by 55% and serum NfL by 50%, with trajectories comparable to known pathogenic variants. Functional decline on the ALSFRS-R slowed from 1.52 points per month pre-treatment to 0.52 points per month post-treatment, muscle strength remained stable, and EQ-VAS quality of life scores remained between 60 and 70. The ability to evaluate treatment response on an individual level will help to determine the clinical relevance of VUS as new gene-targeted treatments for ALS become available.
2026-07-16 | Metabolomic analyses of amyotrophic lateral sclerosis, muscle cramps, and TJ-68 treatment.
Most patients with amyotrophic lateral sclerosis (ALS), a fatal motor neuron disease, experience painful muscle cramps. Our recent pilot trial of the Japanese Kampo medicine TJ-68 suggested its efficacy in improving muscle cramps in patients with ALS. This study analyzed plasma metabolomic changes to identify the underlying mechanisms of muscle cramps in ALS and the effects of TJ-68. Plasma was obtained from 11 participants with ALS in the repeated crossover trial at five time points (baseline, two placebo phases, and two TJ-68 phases). Metabolites were analyzed using mass spectrometry. Linear mixed-effects models were applied to identify metabolite changes associated with muscle cramps, determine the effects of TJ-68 on metabolites, and predict which participants would respond to TJ-68. Higher glutamine/glutamate, arginine, and leucine levels were associated with more severe muscle cramps. TJ-68 treatment increased tryptophan and aconitate levels but reduced serotonin and acetylcarnitine levels. Long-chain acylcarnitine levels were correlated with muscle cramp severity, and their levels tended to decrease with treatment. Uric acid, β-aminoisobutyric acid, α-aminoadipic acid, and acetylcholine emerged as predictors of the efficacy of TJ-68. This study identified the metabolite profile of muscle cramps in ALS and the changes in metabolite levels after TJ-68 treatment. Several baseline metabolites were associated with the prediction of the response to muscle cramps following TJ-68 treatment. Uric acid might be particularly useful because of its easy measurement in standard assays. Our study affirms the value of metabolomic technology for future pharmacotherapy and studies in ALS.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
1 orphan drug designation for Motor neuron disease.
1 orphan drug designation for Motor neuron disease.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Ciliary neurotrophic factor, recombinant human | proteins | FDA | 1992-05-08 | — | Syntex-Synergen Neuroscience |
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