VY9323 / Voyager - LARVOL DELTA

Metabolic alterations in the absence of a neuromuscular phenotype in humanized SOD1A5V mice. (PubMed, Brain Commun) - "Our findings support metabolic dysfunction as an early event in amyotrophic lateral sclerosis pathogenesis. This freely available SOD1A5V model provides a valuable tool for studying amyotrophic lateral sclerosis progression and identifying therapeutic targets for pre-symptomatic treatment."

Journal • Preclinical • Amyotrophic Lateral Sclerosis • CNS Disorders • Metabolic Disorders • SOD1

Antisense oligonucleotide treatment following viral delivery of artificial SOD1-targeting miRNA shows improved efficacy in SOD1-G93A mice. (PubMed, Mol Ther Adv) - "To address this concern, we developed a proof-of-principle study showing that AAV9-amiR-SOD1, in combination with a SOD1-targeting antisense oligonucleotide, provided an additive therapeutic benefit in SOD1-G93A mice compared with AAV9-amiR-SOD1 alone. This combinatorial approach lowered the viral load needed to reach efficacious endpoints, which could mitigate AAV-related adverse events alongside IMS."

Journal • Preclinical • Amyotrophic Lateral Sclerosis • CNS Disorders • Gene Therapies • SOD1

Neural stem cell-derived small extracellular vesicles ameliorate disease progression in the SOD1 G93A murine model of amyotrophic lateral sclerosis. (PubMed, J Neuropathol Exp Neurol) - "Furthermore, by analyzing the RNA-sequencing of muscle specimens from ALS-SOD1 patients, we demonstrated that the rescue effects of NSC-derived EVs might be linked to the p53 pathway. Compared to the PBS control treatment group, both TP53 and the p53 upregulated modulator of apoptosis (PUMA) were downregulated in the spinal cord of mice treated with NSC-derived EVs. These data provide additional knowledge for the promising use of NSC-derived EVs as a potential therapy for ALS."

Journal • Preclinical • Amyotrophic Lateral Sclerosis • CNS Disorders • Respiratory Diseases

Destabilized Soluble SOD1 Species as Potential Determinants of Disease Severity in Familial Amyotrophic Lateral Sclerosis. (PubMed, ACS Chem Neurosci) - "Neither CuATSM nor ebselen─targeting metal binding and disulfide formation, respectively─rescued fluorescence, suggesting broader defects in SOD1 maturation. Nevertheless, both compounds inhibited ferroptosis, a nonapoptotic form of cell death characterized by iron-dependent lipid peroxidation, in HT22 cells, indicating alternative neuroprotective mechanisms. These findings identify destabilized soluble SOD1 species as a key toxic entity in ALS and highlight the utility of GFP-tagged constructs for evaluating folding status and screening therapeutic candidates."

Journal • Amyotrophic Lateral Sclerosis • CNS Disorders • SOD1

Tofersen: A Novel Option for the Treatment of Amyotrophic Lateral Sclerosis. (PubMed, Ann Pharmacother) - "Tofersen provides a promising targeted treatment option for pathogenic SOD1 ALS. Ongoing studies will clarify its long-term clinical impact."

Journal • Review • Amyotrophic Lateral Sclerosis • CNS Disorders • NEFL • Plasma NfL • SOD1

The preclinical discovery and development of edaravone for the treatment of amyotrophic lateral sclerosis: what lessons have we learnt? (PubMed, Expert Opin Drug Discov) - "Clinically, edaravone provides only modest benefits in a subset of patients, reflecting the translational gap between preclinical efficacy and clinical relevance. This case highlights broader challenges of ALS drug discovery, including limited model predictivity, methodological variability, and the lack of patient stratification.The edaravone experience highlights key lessons for future neuroprotective approaches: the importance of standardized preclinical design, integration of human-based models, early pharmacokinetic validation, and biomarker-driven trials to advance precision neuroprotection in ALS."

Journal • Preclinical • Amyotrophic Lateral Sclerosis • Cardiovascular • CNS Disorders • Inflammation • Ischemic stroke

EPISOD1: a phase 1/2, multicenter study to evaluate the safety, tolerability, and exploratory efficacy of intrathecally administered gene therapy AMT-162 in patients with SOD1 amyotrophic lateral sclerosis (SOD1-ALS) (ALS-MND 2025) - P1/2 | "The clinical study EPISOD1 (NCT06100276) presented here is the first-in-human clinical trial using the investigational gene therapy candidate, AMT-162, focused on safety, tolerability, and exploratory efficacy in participants with ALS SOD1 mutations."

Clinical • Gene therapy • P1/2 data • Amyotrophic Lateral Sclerosis • CNS Disorders • Gene Therapies • SOD1

CNS-specific disruption of neuregulin signaling modulates ALS progression (ALS-MND 2025) - "Our goal was to extend findings from the familial ALS SOD1 G93A model to the TDP43 model, which is more representative of sporadic ALS, and to evaluate the efficacy of GlyB4 in patient-derived iPSC microglia—assessing its potential as a broadly applicable therapeutic candidate for sporadic ALS. We report the following findings: (1) CNS administration of GlyB4 preserves motor function in male TDP43 Q331K mice, likely via modulation of the parvalbumin–ErbB signaling axis; (2) selective genetic disruption of NRG1 signaling in microglia increases total TDP43 expression in motor neurons, accelerates disease progression, and reduces survival in TDP43 A315T mice; and (3) GlyB4 effectively inhibits NRG1 receptor activation in iPSC-derived microglia from ALS patients. Collectively, these results provide new mechanistic insights into NRG1-mediated neuron–glia interactions in ALS and support the therapeutic potential of humanized NRG1 antagonists to modify disease progression in..."

Amyotrophic Lateral Sclerosis • CNS Disorders • NRG1 • TARDBP

CASE REPORT: FAMILIAL AMYOTROPHIC LATERAL SCLEROSIS WITH L145S SOD1 MUTATION ON TWO UNRELATED FILIPINOS PRESENTING AS FLAIL LEG SYNDROME (WCN 2025) - "Case 1 was started on Riluzole, Tauroursodeoxycholic acid (TUDCA), Ultrahigh-Dose Methylcobalamin and Edaravone while Case 2 was given Riluzole and Edaravone. ALS SOD1 mutation L145S variant commonly present as flail leg syndrome with slower disease progression. Atypical presentation of ALS like this frequently results to a delay in diagnosis. Gene testing among suspected fALS SOD1 cases can help predict the disease course and potentially receive gene-targeted therapy like Tofersen."

Case report • Clinical • Amyotrophic Lateral Sclerosis • CNS Disorders • SOD1

Exosome Proteomics of SOD1D90A Mutation Suggest Early Disease Mechanisms, and FN1 as a Biomarker. (PubMed, Ann Clin Transl Neurol) - "Exosome proteomics offer a powerful approach to interrogate disease-specific or disease-related proteins that become present in the blood. This helps define the perturbed cellular events with respect to disease progression and reveal potential pharmacokinetic biomarkers. We find FN1 levels to increase with disease progression, suggesting it may be a pharmacokinetic biomarker, especially for ALS patients with prominent UMN loss."

Biomarker • Journal • Amyotrophic Lateral Sclerosis • CNS Disorders • NECTIN1 • SOD1

Cardiac Troponin T in Tofersen-Treated SOD1 ALS Patients: Beginning to Resolve the Catch-22 of Identifying Treatment Responsive Biomarkers in ALS Drug Development. (PubMed, Muscle Nerve) - No abstract available

Biomarker • Journal • Amyotrophic Lateral Sclerosis • CNS Disorders

Improving ALS Molecular Diagnosis Through Functional Assays: Reassessment of a SOD1 Variant of Uncertain Significance. (PubMed, Int J Mol Sci) - "Functional studies demonstrated that this variant leads to cytoplasmic aggregation, reduced neurite outgrowth, and abnormal motor behavior in zebrafish. These results support the systematic use of functional assays to clarify the pathogenicity of uncertain variants, thereby improving diagnostic accuracy, preventing misdiagnosis, and enabling timely therapeutic interventions in ALS."

Journal • Amyotrophic Lateral Sclerosis • CNS Disorders

SOD1 Protein Content in Human Central Nervous System and Peripheral Tissues. (PubMed, J Neurochem) - "The level and activity of SOD1 are not deviating in the areas of the CNS that are most vulnerable to ALS. Instead, insufficient control of SOD1 structure and aggregation could be important factors behind the vulnerability of motor areas to SOD1 proteotoxicity."

Journal • Amyotrophic Lateral Sclerosis • CNS Disorders • SOD1

Modelling Population Genetic Screening in Rare Neurodegenerative Diseases. (PubMed, Biomedicines) - "The risk following a positive screening test was 0.5% for C9orf72 in ALS and 0.4% for HTT in HD when testing repeat expansions, for which the test had sub-optimal performance (sensitivity = 99% and specificity = 90%), and 12.7% for phenylketonuria and 10.9% for ALS SOD1 when testing pathogenic SNVs (sensitivity = 99.96% and specificity = 99.95%)... We show that risk following a positive screening test result can be strikingly low for rare neurological diseases, even for fully penetrant variants such as HTT, if the test has sub-optimal performance. Accordingly, to maximise the utility of screening, it is vital to prioritise protocols with very high sensitivity and specificity, and a careful selection of markers for screening, giving regard to clinical interpretability, actionability, high penetrance, and secondary testing to confirm positive findings."

Journal • Amyotrophic Lateral Sclerosis • CNS Disorders • Huntington's Disease • Metabolic Disorders • Movement Disorders • Phenylketonuria • Rare Diseases

Mapping Glial Autophagy Dynamics in an Amyotrophic Lateral Sclerosis Mouse Model Reveals Microglia and Astrocyte Autophagy Dysfunction. (PubMed, Glia) - "Interestingly, spinal glia showed more pronounced and earlier autophagy dysfunction compared to motor cortex glia, where autophagy dysfunction emerged later in disease end stage, aligning with greater spinal cord pathology reported in this model. Our results suggest that cell-type- and time-specific targeting might be essential when developing autophagy therapeutics for ALS, with prioritization of astrocytic autophagy modulation."

Journal • Preclinical • Amyotrophic Lateral Sclerosis • CNS Disorders • Solid Tumor • SOD1

Voyager Provides Update on SOD1 ALS Gene Therapy Program (GlobeNewswire) - "Voyager Therapeutics... today announced it has decided to assess alternate payloads related to its gene therapy program for superoxide dismutase 1 (SOD1) amyotrophic lateral sclerosis (ALS)....Voyager no longer anticipates filing an investigational new drug (IND) application for VY9323 in mid-2025. Voyager’s cash runway is now expected to extend into mid-2027...We continue to expect IND filings in 2025 for our gene therapy candidates for GBA1 and FA, and in 2026 for VY1706."

IND • Alzheimer's Disease • Amyotrophic Lateral Sclerosis • CNS Disorders

A human-induced pluripotent stem cell (iPSC) line (SMUSHi006-A) from an ALS patient carrying a mutation c.1126C > T in the FUS gene. (PubMed, Stem Cell Res) - "Four major genes associated with ALS-SOD1, TARDBP, FUS, and C9orf72-have been identified, with the fused in sarcoma (FUS) gene demonstrating considerable genetic heterogeneity...The objective of this study is to create another iPS cell line featuring the pathogenic c.1126C > T mutation in the FUS gene. This research aims not only to establish a disease model for ALS linked to FUS mutations but also to pave the way for potential therapeutic interventions."

Journal • Amyotrophic Lateral Sclerosis • CNS Disorders • Oncology • Sarcoma • Solid Tumor • FUS • TARDBP

Tofersen: Hope for the Patient Community and the Importance of Genetic Testing (ALS-MND 2024) - "In Italy, it is estimated that there are about 120 people with the ALS-SOD1 mutation. AISLA has conducted a national survey to understand the reach and impact of genetic testing among people diagnosed with ALS/MND. Join this session to learn more about the current landscape of ALS/MND treatment and the role genetic testing plays in improving patient care."

Clinical • Amyotrophic Lateral Sclerosis • SOD1

Voyager Therapeutics Reports Second Quarter 2024 Financial and Operating Results (GlobeNewswire) - "'Voyager continued to progress our pipeline in the second quarter: we initiated the single ascending dose trial of our anti-tau antibody...and enrollment is on track with top-line safety and pharmacokinetic data expected in H1 2025'...'In parallel, we continued to advance our gene therapy pipeline, and we and our partners are on track to achieve three IND filings in 2025.'...Dosed first participants in Phase 1a single ascending dose (SAD) trial of anti-tau antibody VY7523 (formerly VY-TAU01) for Alzheimer’s disease...VY9323 SOD1 silencing gene therapy program for SOD1 ALS: Voyager expects to file an IND in mid-2025 and initiate a clinical trial in SOD1 ALS patients...Voyager and Neurocrine Biosciences expect to file INDs for the GBA1 and Friedreich’s Ataxia gene therapy programs in 2025, as previously disclosed."

IND • P1 data • Trial status • Alzheimer's Disease • Amyotrophic Lateral Sclerosis • CNS Disorders

Trehalose Protects against Superoxide Dismutase 1 Proteinopathy in an Amyotrophic Lateral Sclerosis Model. (PubMed, Antioxidants (Basel)) - "The survival rates of ALS Sod1 cells stressed in the presence of trehalose were 60% higher than in their absence. Treatment with trehalose after the appearance of Sod1 inclusions in cells expressing WT Sod1 doubled longevity; after 5 days, non-treated cells did not survive, but 15% of cells treated with sugar were still alive. Altogether, our results emphasize the potential of trehalose as a novel therapy, which might be applied preventively in ALS patients with a family history of the disease or after diagnosis in ALS patients who discover the disease following the first symptoms."

Journal • Amyotrophic Lateral Sclerosis • CNS Disorders • Proteinopathy • SOD1

Updates on Disease Mechanisms and Therapeutics for Amyotrophic Lateral Sclerosis. (PubMed, Cells) - "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 SOD1 ALS, the updated C9orf72 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."

Journal • Review • Amyotrophic Lateral Sclerosis • CNS Disorders • TARDBP

Long-term treatment of SOD1 ALS with tofersen: a multicentre experience in 17 patients. (PubMed, J Neurol) - "Clinical findings and NFL analysis strongly suggest that tofersen may have a disease-modifying effect in a subset of SOD1-ALS patients."

Journal • Amyotrophic Lateral Sclerosis • CNS Disorders • CSF NfL • NEFL • SOD1

Voyager Therapeutics Presents Data for Second-Generation, TRACER-Generated Capsids and CNS Gene Therapy Programs Advancing Toward Clinical Trials at the ASGCT 27th Annual Meeting (GlobeNewswire) - "A potent SOD1 RNAi transgene...led to a favorable safety profile and significant reductions of SOD1 mRNA in critical spinal cord and brain regions impacted in ALS, supporting continued development and advancement into clinical testing. Voyager anticipates filing an IND application in this program in mid-2025."

IND • Amyotrophic Lateral Sclerosis • CNS Disorders

Optimized Artificial miRNAs Delivered by AAV9 Dramatically Improve Survival, Respiratory and Motor Functions of SOD1G93A‐ALS Mice (ESGCT 2023) - "Thus, a single intravascular injection of AAV9-hSMN1-dual-amiR vector in 60-68 days old SOD1G93A mice significantly reduces SOD1 expression within CNS and non-CNS tissues, efficiently preserves respiratory and motor functions, and extends the survival by 94 days which has not been reported for this SOD1-G93A mice. These results suggest that a clinical evaluation of this strategy is warranted."

Preclinical • Amyotrophic Lateral Sclerosis • CNS Disorders • Cytomegalovirus Infection • SOD1

Optimized Artificial miRNAs Delivered by rAAV9 Dramatically Improve Survival, Respiratory and Motor Functions of SOD1G93A-ALS Mice (ASGCT 2024) - "While current treatments such as gene silencing using ASO or siRNA have shown limited clinical benefits with the need for repeated dosing, our study explores the use of Adeno-Associated Virus serotype 9 (AAV9) for the delivery of optimized artificial microRNAs (amiRs) targeting SOD1 in a single-doses treatment for ALS-SOD1...Here we use a single intravenous injection of a AAV9 vector significantly reduces SOD1 expression within CNS and non-CNS tissues, effectively preserves respiratory and motor functions, and extends survival by 98.5 days, 39 days, and 22 days when administered at the asymptomatic, non-motor symptomatic and motor symptomatic stages in SOD1G93A mice, respectively. These therapeutic outcomes, unprecedented in SOD1G93A mice, suggested the need for a clinical evaluation of this promising treatment strategy."

Preclinical • Amyotrophic Lateral Sclerosis • CNS Disorders • Respiratory Diseases • MIR33 • SOD1