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Despite extensive research, amyotrophic lateral sclerosis (ALS) remains a progressive and invariably fatal neurodegenerative disease. Limited knowledge of the underlying causes of ALS has made it difficult to target upstream biological mechanisms of disease, and therapeutic interventions are usually administered relatively late in the course of disease. Genetic forms of ALS offer a unique opportunity for therapeutic development, as genetic associations may reveal potential insights into disease etiology. Genetic ALS may also be amenable to investigating earlier intervention given the possibility of identifying clinically presymptomatic, at-risk individuals with causative genetic variants. There is increasing evidence for a presymptomatic phase of ALS, with biomarker data from the Pre-Symptomatic Familial ALS (Pre-fALS) study showing that an elevation in blood neurofilament light chain (NfL) precedes phenoconversion to clinically manifest disease. Tofersen is an investigational antisense oligonucleotide designed to reduce synthesis of superoxide dismutase 1 (SOD1) protein through degradation of SOD1 mRNA. Informed by Pre-fALS and the tofersen clinical development program, the ATLAS study (NCT04856982) is designed to evaluate the impact of initiating tofersen in presymptomatic carriers of SOD1 variants associated with high or complete penetrance and rapid disease progression who also have biomarker evidence of disease activity (elevated plasma NfL). The ATLAS study will investigate whether tofersen can delay the emergence of clinically manifest ALS. To our knowledge, ATLAS is the first interventional trial in presymptomatic ALS and has the potential to yield important insights into the design and conduct of presymptomatic trials, identification, and monitoring of at-risk individuals, and future treatment paradigms in ALS.

Antibody-mediated encephalitis defines a class of diseases wherein antibodies directed at cell-surface receptors are associated with behavioral and cognitive disturbances. One such recently described encephalitis is due to antibodies directed at alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR). This entity is exceptionally rare and its clinical phenotype incompletely described. We present findings from two cases of AMPAR encephalitis that exemplify variability in the disease spectrum, and summarize findings in published cases derived from a systematic literature review. When all patients are considered together, the presence of psychiatric symptoms at presentation portended a poor outcome and was associated with the presence of a tumor. Furthermore, we provide evidence to suggest that the topography of magnetic resonance imaging abnormalities in reported cases mirrors the distribution of AMPARs in the human brain. The potential for neurological improvement following immunomodulatory therapy together with the favorable outcome reported in most cases emphasizes the importance of testing for autoantibodies against neuronal cell-surface proteins, including AMPAR, in patients with clinical and neuroimaging findings suggestive of autoimmune encephalitis. Close attention to the clinical phenotype may inform the presence of malignancy and long-term prognosis.

Objective Patients with amyotrophic lateral sclerosis (ALS) caused by superoxide dismutase 1 (SOD1) gene mutations (SOD1 ALS) treated with tofersen have shown slowing of disease progression, and disease stabilization with recovery of function in some patients. We report our clinical experience with treating patients with SOD1 ALS and the effects of tofersen on outcome measures. Methods This was a single‐center observational study of patients with SOD1 ALS receiving treatment with tofersen. The effects of tofersen treatment on neurofilament levels, muscle strength, and clinical outcome measures were assessed. Several patients had outpatient neuromuscular rehabilitation in addition to tofersen treatment and we report changes in functional outcomes. Results Seven SOD1 ALS patients received treatment at our institution. All patients showed robust and sustained declines in serum NfL and CSF pNFH (mean change serum NfL: −57.9%; mean change CSF pNFH: −67.6%). There was apparent disease stabilization as assessed by the ALSFRS‐R total score, mean change 1.1 (SD = 0.7). There was notable improvement in functional independence measured by the FIM motor score, mean change 5.13 points (SD = 3.85). Interpretation This study provides evidence that tofersen treatment in SOD1 ALS can lead to meaningful preservation of function and suggestions of sustained improvement in neurologic function in some patients, and strongly supports the role of neurofilaments as therapeutic biomarkers.

In a phase 1–2 dose-escalation trial involving adults with ALS due to SOD1 mutations who received intrathecal tofersen (an antisense oligonucleotide) or placebo, the levels of mutant SOD1 in the CSF were 33 percentage points lower in the highest-dose tofersen group than in the placebo group.

The antisense molecule tofersen was tested intrathecally in 108 patients with ALS due to SOD1 mutations. In a subgroup with faster-progressing disease, there was no clinical difference from placebo over a period of 28 weeks.

BACKGROUNDWolfram syndrome is a rare ER disorder characterized by insulin-dependent diabetes mellitus, optic nerve atrophy, and progressive neurodegeneration. Although there is no treatment for Wolfram syndrome, preclinical studies in cell and rodent models suggest that therapeutic strategies targeting ER calcium homeostasis, including dantrolene sodium, may be beneficial.METHODSBased on results from preclinical studies on dantrolene sodium and ongoing longitudinal studies, we assembled what we believe is the first-ever clinical trial in pediatric and adult Wolfram syndrome patients with an open-label phase Ib/IIa trial design. The primary objective was to assess the safety and tolerability of dantrolene sodium in adult and pediatric Wolfram syndrome patients. Secondary objectives were to evaluate the efficacy of dantrolene sodium on residual pancreatic β cell functions, visual acuity, quality-of-life measures related to vision, and neurological functions.RESULTSDantrolene sodium was well tolerated by Wolfram syndrome patients. Overall, β cell functions were not significantly improved, but there was a significant correlation between baseline β cell functions and change in β cell responsiveness (R2, P = 0.004) after 6-month dantrolene therapy. Visual acuity and neurological functions were not improved by 6-month dantrolene sodium. Markers of inflammatory cytokines and oxidative stress, such as IFN-γ, IL-1β, TNF-α, and isoprostane, were elevated in subjects.CONCLUSIONThis study justifies further investigation into using dantrolene sodium and other small molecules targeting the ER for treatment of Wolfram syndrome.TRIAL REGISTRATIONClinicalTrials.gov identifier NCT02829268FUNDINGNIH/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (DK112921, DK113487, DK020579), NIH/National Center for Advancing Translational Sciences (NCATS) (TR002065, TR000448), NIH training grant (F30DK111070), Silberman Fund, Ellie White Foundation, Snow Foundation, Unravel Wolfram Syndrome Fund, Stowe Fund, Eye Hope Foundation, Feiock Fund, Washington University Institute of Clinical and Translational Sciences grant UL1TR002345 from NIH/NCATS, Bursky Center for Human Immunology & Immunotherapy Programs.

Objective To define the clinicopathologic features and diagnostic utility associated with anti‐cytosolic 5′‐nucleotidase 1A (NT5C1A) antibody seropositivity in idiopathic inflammatory myopathies (IIMs). Methods Anti‐NT5C1A antibody status was clinically tested between 2014 and 2019 in the Washington University neuromuscular clinical laboratory. Using clinicopathologic information available for 593 patients, we classified them as inclusion body myositis (IBM), dermatomyositis, antisynthetase syndrome, immune‐mediated necrotizing myopathy (IMNM), nonspecific myositis, or noninflammatory muscle diseases. Results Of 593 patients, anti‐NT5C1A antibody was found in 159/249 (64%) IBM, 11/53 (21%) dermatomyositis, 7/27 (26%) antisynthetase syndrome, 9/76 (12%) IMNM, 20/84 (24%) nonspecific myositis, and 6/104 (6%) noninflammatory muscle diseases patients. Among patients with IBM, anti‐NT5C1A antibody seropositive patients had more cytochrome oxidase‐negative fibers compared with anti‐NT5C1A antibody seronegative patients. Among 14 IBM patients initially negative for anti‐NT5C1A antibody, three patients (21%) converted to positive. Anti‐NT5C1A antibody seropositivity did not correlate with malignancy, interstitial lung disease, response to treatments in dermatomyositis, antisynthetase syndrome, and IMNM, or survival in IIMs. Interpretation Anti‐NT5C1A antibody is associated with IBM. However, the seropositivity can also be seen in non‐IBM IIMs and it does not correlate with any prognostic factors or survival.

Objective Accumulation of misfolded superoxide dismutase‐1 (SOD1) is a pathological hallmark of SOD1‐related amyotrophic lateral sclerosis (ALS) and is observed in sporadic ALS where its role in pathogenesis is controversial. Understanding in vivo protein kinetics may clarify how SOD1 influences neurodegeneration and inform optimal dosing for therapies that lower SOD1 transcripts. Methods We employed stable isotope labeling paired with mass spectrometry to evaluate in vivo protein kinetics and concentration of soluble SOD1 in cerebrospinal fluid (CSF) of SOD1 mutation carriers, sporadic ALS participants and controls. A deaminated SOD1 peptide, SDGPVKV, that correlates with protein stability was also measured. Results In participants with heterozygous SOD1A5V mutations, known to cause rapidly progressive ALS, mutant SOD1 protein exhibited ~twofold faster turnover and ~ 16‐fold lower concentration compared to wild‐type SOD1 protein. SDGPVKV levels were increased in SOD1A5V carriers relative to controls. Thus, SOD1 mutations impact protein kinetics and stability. We applied this approach to sporadic ALS participants and found that SOD1 turnover, concentration, and SDGPVKV levels are not significantly different compared to controls. Interpretation These results highlight the ability of stable isotope labeling approaches and peptide deamidation to discern the influence of disease mutations on protein kinetics and stability and support implementation of this method to optimize clinical trial design of gene and molecular therapies for neurological disorders. Trial Registration Clinicaltrials.gov: NCT03449212.

ObjectivesAutoimmune encephalitis (AE) is increasingly recognized as an important cause of subacute cognitive decline, seizures, and encephalopathy, with an ever-broadening clinical phenotype. Sleep disturbances are reported in AE patients, including rapid eye movement sleep behavior disorder, hypersomnia, fragmented sleep, and sleep-disordered breathing; however, the prevalence of sleep disturbances and contributions to outcomes in AE patients remain unknown. There is a need to determine the prevalence of sleep disturbances in AE patients, and to clarify the relationship between specific autoantibodies and disruptions in sleep.MethodsClinical history, results of serum and cerebrospinal fluid testing, electroencephalography, and neuroimaging were reviewed from 26 AE patients diagnosed and managed at our tertiary care hospital. Polysomnography was performed in patients with clinical indications, yielding data from 12 patients.ResultsThe median age of AE patients was 53 years (range 18–83). Autoantibodies against intracellular antigens (including Ma and Hu autoantibodies) were identified in 6/26 (23%) patients, while autoantibodies against cell-surface neuronal antigens (including NMDAR and LGI1) were identified in 20/26 (77%) patients. New sleep complaints were reported by 19/26 (73%) AE patients, including gasping or snoring (9/19, 47%), dream enactment behavior (6/19, 32%), insomnia (5/19, 29%), hypersomnia (4/19, 21%), other parasomnias (4/19, 21%), and dream-wake confusional states (2/19, 11%). Dream enactment behaviors were particularly common in AE associated with LGI1 autoantibodies, reported in 4/7 (57%) patients. Polysomnography showed reduced total sleep time, stage 3 and rapid eye movement sleep, and prominent sleep fragmentation.ConclusionSleep disturbances are common in AE, warranting active surveillance in affected patients. Improved identification and treatment of sleep disorders may reduce morbidity associated with AE and improve long-term outcomes.

Hexanucleotide repeat expansion of C9orf72 is a common genetic cause of amyotrophic lateral sclerosis (ALS). No C9orf72-targeted treatments are available. BIIB078 is an investigational antisense oligonucleotide targeting C9orf72 sense RNA. We aimed to assess the safety, tolerability, and pharmacokinetics of BIIB078 in participants with C9orf72-associated ALS. This phase 1, randomised controlled trial was done at 22 sites in six countries (Canada, Ireland, Netherlands, Switzerland, UK, and USA). Adults with ALS and a pathogenic repeat expansion in C9orf72 were randomly assigned within six cohorts, via Interactive Response Technology in a 3:1 ratio per cohort, to receive BIIB078 (5 mg, 10 mg, 20 mg, 35 mg, 60 mg, or 90 mg in cohorts 1–6, respectively) or placebo, via an intrathecal bolus injection. The treatment period consisted of three loading doses of study treatment, administered approximately once every 2 weeks, followed by monthly maintenance doses during a treatment period of about 3 months for cohorts 1–3 and about 6 months for cohorts 4–6. Patients and investigators were masked to treatment assignment. The primary endpoint was the incidence of adverse events and serious adverse events. This trial was registered with ClinicalTrials.gov (NCT03626012) and is completed. Between Sept 10, 2018, and Nov 17, 2021, 124 patients were screened for inclusion in the study. 18 patients were excluded and 106 participants were enrolled and randomly assigned to receive 5 mg (n=6), 10 mg (n=9), 20 mg (n=9), 35 mg (n=19), 60 mg (n=18), or 90 mg (n=18) of BIIB078, or placebo (n=27). 58 (55%) of 106 patients were female. All patients received at least one dose of study treatment and were included in all analyses. All participants had at least one adverse event; most adverse events were mild or moderate in severity and did not lead to treatment discontinuation. The most common adverse events in BIIB078-treated participants were falls, procedural pain, headache, and post lumbar puncture syndrome. 14 (18%) of 79 patients who received any dose of BIIB078 reported serious adverse events, compared with nine (33%) of 27 patients who received placebo. Five participants who received BIIB078 and three participants who received placebo had fatal adverse events: respiratory failure in a participant who received 10 mg BIIB078, ALS worsening in two participants who received 35 mg BIIB078, traumatic intracerebral haemorrhage in one participant who received 35 mg BIIB078, pulmonary embolism in one participant who received 60 mg BIIB078, and respiratory failure in three participants who received placebo. All deaths were assessed as not related to the study treatment by the reporting investigator. On the basis of these phase 1 study results, including secondary and exploratory findings showing no reduction in neurofilament levels and no benefit on clinical outcomes relative to the placebo cohort, BIIB078 clinical development has been discontinued. However, these results will be informative in furthering our understanding of the complex pathobiology of C9orf72-associated ALS. Biogen.