Publications by authors named "Philip Van Damme"

214 Publications

RNF170 mutation causes autosomal dominant sensory ataxia with variable pyramidal involvement.

Eur J Neurol 2021 Sep 1. Epub 2021 Sep 1.

Department of Neurosciences, Experimental Neurology, and Leuven Brain Institute (LBI), KU Leuven - University of Leuven, Leuven, Belgium.

Background: Although hereditary ataxias are a group of clinically and genetically heterogeneous disorders, specific clinical clues can sometimes incriminate certain genes. This can trigger genetic testing in sporadic patients or prompt dissecting certain genes more thoroughly when initial genetic testing is negative. Also for the assembly of gene panels and interpretation of the results, genotype-phenotype correlations remain important to establish.

Methods: We clinically evaluated a Belgian family with autosomal dominant inherited sensory ataxia and variable pyramidal involvement and performed targeted clinical exome sequencing. Secondly, we retrospectively screened sequencing data of an in-house cohort of 404 patients with neuromuscular disorders for variants in the identified gene RNF170.

Results: All affected family members showed sensory ataxia on examination. Pyramidal involvement, and sometimes slow-pursuit abnormalities and/or a sensory neuropathy, were more variable findings. We identified the heterozygous variant p.Arg199Cys in RNF170 in all three affected siblings of our family. We did not find additional pathogenic variants in RNF170 in our in-house neuromuscular cohort.

Conclusions: We confirm the heterozygous variant p.Arg199Cys in RNF170 in a Belgian family with autosomal dominant sensory ataxia and variable pyramidal involvement. This constitutes a rare but clinically recognizable phenotype that warrants testing of RNF170. Unlike the distinctive bi-allelic loss of function variants in RNF170 associated with hereditary spastic paraplegia (HSP), the p.Arg199Cys variant is the only one reported in sensory ataxia. It is important for neurologists to be aware of this characteristic phenotype and to include this gene in gene panels for ataxia and HSP.
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http://dx.doi.org/10.1111/ene.15091DOI Listing
September 2021

Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis.

JAMA Neurol 2021 Aug 30. Epub 2021 Aug 30.

Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.

Importance: Juvenile amyotrophic lateral sclerosis (ALS) is a rare form of ALS characterized by age of symptom onset less than 25 years and a variable presentation.

Objective: To identify the genetic variants associated with juvenile ALS.

Design, Setting, And Participants: In this multicenter family-based genetic study, trio whole-exome sequencing was performed to identify the disease-associated gene in a case series of unrelated patients diagnosed with juvenile ALS and severe growth retardation. The patients and their family members were enrolled at academic hospitals and a government research facility between March 1, 2016, and March 13, 2020, and were observed until October 1, 2020. Whole-exome sequencing was also performed in a series of patients with juvenile ALS. A total of 66 patients with juvenile ALS and 6258 adult patients with ALS participated in the study. Patients were selected for the study based on their diagnosis, and all eligible participants were enrolled in the study. None of the participants had a family history of neurological disorders, suggesting de novo variants as the underlying genetic mechanism.

Main Outcomes And Measures: De novo variants present only in the index case and not in unaffected family members.

Results: Trio whole-exome sequencing was performed in 3 patients diagnosed with juvenile ALS and their parents. An additional 63 patients with juvenile ALS and 6258 adult patients with ALS were subsequently screened for variants in the SPTLC1 gene. De novo variants in SPTLC1 (p.Ala20Ser in 2 patients and p.Ser331Tyr in 1 patient) were identified in 3 unrelated patients diagnosed with juvenile ALS and failure to thrive. A fourth variant (p.Leu39del) was identified in a patient with juvenile ALS where parental DNA was unavailable. Variants in this gene have been previously shown to be associated with autosomal-dominant hereditary sensory autonomic neuropathy, type 1A, by disrupting an essential enzyme complex in the sphingolipid synthesis pathway.

Conclusions And Relevance: These data broaden the phenotype associated with SPTLC1 and suggest that patients presenting with juvenile ALS should be screened for variants in this gene.
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http://dx.doi.org/10.1001/jamaneurol.2021.2598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8406220PMC
August 2021

Tweaking Progranulin Expression: Therapeutic Avenues and Opportunities.

Front Mol Neurosci 2021 23;14:713031. Epub 2021 Jul 23.

Department of Neurosciences, Experimental Neurology and Leuven Brain Institute (LBI), KU Leuven-University of Leuven, Leuven, Belgium.

Frontotemporal dementia (FTD) is a neurodegenerative disease, leading to behavioral changes and language difficulties. Heterozygous loss-of-function mutations in () induce haploinsufficiency of the protein and are associated with up to one-third of all genetic FTD cases worldwide. While the loss of GRN is primarily associated with neurodegeneration, the biological functions of the secreted growth factor-like protein are more diverse, ranging from wound healing, inflammation, vasculogenesis, and metabolic regulation to tumor cell growth and metastasis. To date, no disease-modifying treatments exist for FTD, but different therapeutic approaches to boost GRN levels in the central nervous system are currently being developed (including AAV-mediated gene delivery as well as anti-SORT1 antibody therapy). In this review, we provide an overview of the multifaceted regulation of GRN levels and the corresponding therapeutic avenues. We discuss the opportunities, advantages, and potential drawbacks of the diverse approaches. Additionally, we highlight the therapeutic potential of elevating GRN levels beyond patients with loss-of-function mutations in .
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http://dx.doi.org/10.3389/fnmol.2021.713031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8343103PMC
July 2021

Innovating Clinical Trials for Amyotrophic Lateral Sclerosis: Challenging the Established Order.

Neurology 2021 Sep 27;97(11):528-536. Epub 2021 Jul 27.

From the Department of Neurology, UMC Utrecht Brain Center (R.P.A.v.E., T.K., A.D.d.J., H.-J.W., L.H.v.d.B.), and Biostatistics & Research Support, Julius Center for Health Sciences and Primary Care (R.P.A.E., S.N., M.J.C.E.), University Medical Center Utrecht; Department of Health Evidence (K.C.B.R.), Section Biostatistics, Radboud Medical Centre Nijmegen, the Netherlands; Biostatistics (L.K.), GlaxoSmithKline R&D, Stevenage, UK; Neurosciences (S.S.H.), Takeda Pharmaceuticals, Cambridge, MA; Discovery Medicine (S.S.H., N.E.), GlaxoSmithKline R&D, Upper Providence, PA; Clinical Development (A.L.), Novartis Gene Therapies; Clinical Translational Medicine (A.L.), Future Pipeline Discovery, GlaxoSmithKline R&D, Middlesex; Maurice Wohl Clinical Neuroscience Institute and United Kingdom Dementia Research Institute Centre, Department of Basic and Clinical Neuroscience, King's College London (A.A.-C.); Department of Neurology (A.A.-C.), King's College Hospital, London, UK; Department of Neurosciences (P.V.D.), Laboratory for Neurobiology, KU Leuven and Center for Brain & Disease Research, VIB, Leuven Brain Institute; Department of Neurology (P.V.D.), University Hospitals Leuven, Belgium; Department of Neurology (O.H.), National Neuroscience Centre, Beaumont Hospital, Dublin, Ireland; FutureNeuro SFI Research Centre (O.H.), Royal College of Surgeons in Ireland, Dublin; and Department of Neuroscience (P.J.S., C.J.M.), Sheffield Institute for Translational Neuroscience, University of Sheffield, UK.

Development of effective treatments for amyotrophic lateral sclerosis (ALS) has been hampered by disease heterogeneity, a limited understanding of underlying pathophysiology, and methodologic design challenges. We have evaluated 2 major themes in the design of pivotal, phase 3 clinical trials for ALS-(1) patient selection and (2) analytical strategy-and discussed potential solutions with the European Medicines Agency. Several design considerations were assessed using data from 5 placebo-controlled clinical trials (n = 988), 4 population-based cohorts (n = 5,100), and 2,436 placebo-allocated patients from the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database. The validity of each proposed design modification was confirmed by means of simulation and illustrated for a hypothetical setting. Compared to classical trial design, the proposed design modifications reduce the sample size by 30.5% and placebo exposure time by 35.4%. By making use of prognostic survival models, one creates a potential to include a larger proportion of the population and maximize generalizability. We propose a flexible design framework that naturally adapts the trial duration when inaccurate assumptions are made at the design stage, such as enrollment or survival rate. In case of futility, the follow-up time is shortened and patient exposure to ineffective treatments or placebo is minimized. For diseases such as ALS, optimizing the use of resources, widening eligibility criteria, and minimizing exposure to futile treatments and placebo is critical to the development of effective treatments. Our proposed design modifications could circumvent important pitfalls and may serve as a blueprint for future clinical trials in this population.
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http://dx.doi.org/10.1212/WNL.0000000000012545DOI Listing
September 2021

Distinguishing Primary Lateral Sclerosis from Parkinsonian Syndromes with the Help of Advanced Imaging.

J Nucl Med 2021 Sep 20;62(9):1318-1319. Epub 2021 May 20.

Neuromuscular Reference Centre, Department of Neurology, University Hospitals Leuven, Leuven, Belgium;

We describe a unique case of a patient presenting with unilateral mild paresis, slowing of the upper limb, and parkinsonism, who underwent a full imaging work-up including MRI, I-FP-CIT PET, F-FE-PE2I PET, and F-FDG PET. This case demonstrates that imaging may aid substantially in the diagnostic work-up of complex neurologic disorders.
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http://dx.doi.org/10.2967/jnumed.121.261942DOI Listing
September 2021

Intracerebroventricular delivery of vascular endothelial growth factor in patients with amyotrophic lateral sclerosis, a phase I study.

Brain Commun 2020 29;2(2):fcaa160. Epub 2020 Sep 29.

Department of Neurosciences, KU Leuven - University of Leuven, Leuven, Belgium.

We studied the feasibility, safety, tolerability and pharmacokinetics of intracerebroventricular delivery of recombinant human vascular endothelial growth factor in patients with amyotrophic lateral sclerosis. In this phase I study in patients with amyotrophic lateral sclerosis, the study drug was delivered using an implantable programmable pump connected to a catheter inserted in the frontal horn of the lateral cerebral ventricle. A first cohort received open label vascular endothelial growth factor (0.2, 0.8 and 2 µg/day), a second cohort received placebo, 0.8 or 2 µg/day of study dug. After the 3-month study period, all patients could participate in an open label extension study. In total, 18 patients with amyotrophic lateral sclerosis, seen at the University Hospitals in Leuven were included. The surgical procedure was well tolerated in most patients. One patient had transient postoperative seizures, due to an ischemic lesion along the catheter tract. The first 3-month study period was completed by 15/18 patients. Administration of 2 µg/day vascular endothelial growth factor resulted in sustained detectable levels in cerebrospinal fluid. A pulmonary embolus occurred in 3 patients, in 1 patient in the first 3-month study, and in 2 patients during the open label extension study. The study drug was well tolerated in the other patients, for up to 6 years in the open label extension study. Our study shows that intracerebroventricular administration of 2 µg/day of vascular endothelial growth factor to patients with amyotrophic lateral sclerosis is feasible, results in detectable cerebrospinal fluid levels and is well tolerated in most patients. The most common serious adverse event was a pulmonary embolus.
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http://dx.doi.org/10.1093/braincomms/fcaa160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099230PMC
September 2020

Liquid-Liquid Phase Separation Enhances TDP-43 LCD Aggregation but Delays Seeded Aggregation.

Biomolecules 2021 04 8;11(4). Epub 2021 Apr 8.

Department of Neurosciences, Experimental Neurology and Leuven Brain Institute (LBI), KU Leuven-University of Leuven, 3000 Leuven, Belgium.

Aggregates of TAR DNA-binding protein (TDP-43) are a hallmark of several neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). Although TDP-43 aggregates are an undisputed pathological species at the end stage of these diseases, the molecular changes underlying the initiation of aggregation are not fully understood. The aim of this study was to investigate how phase separation affects self-aggregation and aggregation seeded by pre-formed aggregates of either the low-complexity domain (LCD) or its short aggregation-promoting regions (APRs). By systematically varying the physicochemical conditions, we observed that liquid-liquid phase separation (LLPS) promotes spontaneous aggregation. However, we noticed less efficient seeded aggregation in phase separating conditions. By analyzing a broad range of conditions using the Hofmeister series of buffers, we confirmed that stabilizing hydrophobic interactions prevail over destabilizing electrostatic forces. RNA affected the cooperativity between LLPS and aggregation in a "reentrant" fashion, having the strongest positive effect at intermediate concentrations. Altogether, we conclude that conditions which favor LLPS enhance the subsequent aggregation of the TDP-43 LCD with complex dependence, but also negatively affect seeding kinetics.
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http://dx.doi.org/10.3390/biom11040548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8068378PMC
April 2021

Human motor units in microfluidic devices are impaired by FUS mutations and improved by HDAC6 inhibition.

Stem Cell Reports 2021 Sep 22;16(9):2213-2227. Epub 2021 Apr 22.

KU Leuven - University of Leuven, Department of Neurosciences, Experimental Neurology, and Leuven Brain Institute, Leuven, Belgium; VIB, Center for Brain & Disease Research, Laboratory of Neurobiology, Leuven, Belgium. Electronic address:

Neuromuscular junctions (NMJs) ensure communication between motor neurons (MNs) and muscle; however, in MN disorders, such as amyotrophic lateral sclerosis (ALS), NMJs degenerate resulting in muscle atrophy. The aim of this study was to establish a versatile and reproducible in vitro model of a human motor unit to investigate the effects of ALS-causing mutations. Therefore, we generated a co-culture of human induced pluripotent stem cell (iPSC)-derived MNs and human primary mesoangioblast-derived myotubes in microfluidic devices. A chemotactic and volumetric gradient facilitated the growth of MN neurites through microgrooves resulting in the interaction with myotubes and the formation of NMJs. We observed that ALS-causing FUS mutations resulted in reduced neurite outgrowth as well as an impaired neurite regrowth upon axotomy. NMJ numbers were likewise reduced in the FUS-ALS model. Interestingly, the selective HDAC6 inhibitor, Tubastatin A, improved the neurite outgrowth, regrowth, and NMJ morphology, prompting HDAC6 inhibition as a potential therapeutic strategy for ALS.
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http://dx.doi.org/10.1016/j.stemcr.2021.03.029DOI Listing
September 2021

Altered perivascular fibroblast activity precedes ALS disease onset.

Nat Med 2021 04 15;27(4):640-646. Epub 2021 Apr 15.

University of Ulm, Neurology Clinic, Ulm, Germany.

Apart from well-defined factors in neuronal cells, only a few reports consider that the variability of sporadic amyotrophic lateral sclerosis (ALS) progression can depend on less-defined contributions from glia and blood vessels. In this study we use an expression-weighted cell-type enrichment method to infer cell activity in spinal cord samples from patients with sporadic ALS and mouse models of this disease. Here we report that patients with sporadic ALS present cell activity patterns consistent with two mouse models in which enrichments of vascular cell genes preceded microglial response. Notably, during the presymptomatic stage, perivascular fibroblast cells showed the strongest gene enrichments, and their marker proteins SPP1 and COL6A1 accumulated in enlarged perivascular spaces in patients with sporadic ALS. Moreover, in plasma of 574 patients with ALS from four independent cohorts, increased levels of SPP1 at disease diagnosis repeatedly predicted shorter survival with stronger effect than the established risk factors of bulbar onset or neurofilament levels in cerebrospinal fluid. We propose that the activity of the recently discovered perivascular fibroblast can predict survival of patients with ALS and provide a new conceptual framework to re-evaluate definitions of ALS etiology.
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http://dx.doi.org/10.1038/s41591-021-01295-9DOI Listing
April 2021

-derived arginine-containing dipeptide repeats associate with axonal transport machinery and impede microtubule-based motility.

Sci Adv 2021 Apr 9;7(15). Epub 2021 Apr 9.

KU Leuven-University of Leuven, Department of Neurosciences, Experimental Neurology and Leuven Brain Institute (LBI), Leuven, Belgium.

A hexanucleotide repeat expansion in the gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). How this mutation leads to these neurodegenerative diseases remains unclear. Here, we show using patient stem cell-derived motor neurons that the repeat expansion impairs microtubule-based transport, a process critical for neuronal survival. Cargo transport defects are recapitulated by treating neurons from healthy individuals with proline-arginine and glycine-arginine dipeptide repeats (DPRs) produced from the repeat expansion. Both arginine-rich DPRs similarly inhibit axonal trafficking in adult neurons in vivo. Physical interaction studies demonstrate that arginine-rich DPRs associate with motor complexes and the unstructured tubulin tails of microtubules. Single-molecule imaging reveals that microtubule-bound arginine-rich DPRs directly impede translocation of purified dynein and kinesin-1 motor complexes. Collectively, our study implicates inhibitory interactions of arginine-rich DPRs with axonal transport machinery in -associated ALS/FTD and thereby points to potential therapeutic strategies.
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http://dx.doi.org/10.1126/sciadv.abg3013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034861PMC
April 2021

Detection of multiple myositis-specific autoantibodies in unique patients with idiopathic inflammatory myopathy: A single centre-experience and literature review: Systematic review.

Semin Arthritis Rheum 2021 04 27;51(2):486-494. Epub 2021 Mar 27.

Rheumatology, University Hospitals Leuven, Leuven, Belgium; KU Leuven Department of Development and Regeneration, Skeletal Biology and Engineering Research Centre, Laboratory of Tissue Homeostasis and Disease. Electronic address:

Introduction: Myositis-specific autoantibodies (MSAs) are thought to be mutually exclusive in patients with idiopathic inflammatory myopathies (IIM) based on studies with immunoprecipitation-based (IP) detection methods. Recently, detection of multiple MSAs in unique patients is increasingly reported, but the extent of this phenomenon remains unclear.

Methods: At our centre, we reviewed results from two line immunoassays and one dot immunoassay in 145 IIM patients and 240 controls for the presence of multiple MSAs. Pubmed and Embase were systematically searched for articles mentioning detection of multiple MSAs in IIM patients, published until February 2019. We assessed the frequency, detection method, the precise combinations and clinical phenotypes of participants with multiple MSAs.

Results: At our centre, detection of multiple MSAs occurred in 3.4-8.3% of patients with IIM, depending on the assay. However, no cases with full concordance across all three assays were identified. Forty-four articles reported detection of multiple MSAs, representing a total of 133 cases, including four patients with a connective tissue disease other than IIM and two healthy controls. In 101 cases all MSAs were detected using only one detection method: 40 cases with IP-based methods (most frequently used technique) and 61 cases with other assay types. In most cases the phenotype of patients with multiple MSAs matched the predicted presentation associated with one MSA and in few cases the phenotype matched with both MSAs.

Conclusion: Detection of multiple MSAs in unique IIM patients is less rare than commonly accepted. Specificity issues of the commercially available multiplex immunoassays may, at least partly, explain the higher frequency compared to IP-based methods. 'True multiple MSA-positive' patients may exist, though they are most likely rare.
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http://dx.doi.org/10.1016/j.semarthrit.2021.03.012DOI Listing
April 2021

Prognostic value of neurofilament light chain in chronic inflammatory demyelinating polyneuropathy.

Brain Commun 2021 9;3(1):fcab018. Epub 2021 Mar 9.

Department of Neurosciences, Laboratory for Molecular Neurobiomarker Research, Leuven Brain Institute, KU Leuven, Leuven 3000, Belgium.

Chronic inflammatory demyelinating polyneuropathy is a neuroinflammatory disorder with considerable variation in clinical phenotype, disease progression and therapy response among patients. Recently, paranodal antibodies associated with poor response to intravenous immunoglobulin therapy and more aggressive disease course have been described in small subsets of patients, but reliable serum-based prognostic biomarkers are not yet available for the general population. In current retrospective longitudinal study, we utilized logistic regression models to investigate the associations of serum neurofilament light chain levels with 1-year disease progression and therapy response during follow-up in chronic inflammatory demyelinating polyneuropathy. One-year disease progression was defined as a decrease of four or more points (the minimal clinically important difference) on an 80-point Medical Research Council sum-score scale 1 year after sampling. Patients who, compared to treatment received at time of sampling, required therapy switch during follow-up due to insufficient effect were classified as non-responders. Serum neurofilament light chain was measured by electrochemiluminescence assay in clinical residual serum samples of 76 patients diagnosed with probable (13 patients) or definite (63 patients) chronic inflammatory demyelinating polyneuropathy according to European Federation of Neurological Societies/Peripheral Nerve Society diagnostic criteria. Eleven (15%) patients were female, and the mean (standard deviation) cohort age was 61.5 (11.7) years. In both univariate and multivariable (including demographics) models, elevated serum neurofilament light chain harboured increased odds for 1-year disease progression (respectively odds ratio, 1.049; 95% confidence interval, 1.022-1.084 and odds ratio, 1.097; 95% confidence interval, 1.045-1.169; both   0.001). Patients with levels above the median cohort neurofilament light chain level (28.3 pg/ml) had largely increased odds of 1-year disease progression (univariate: odds ratio, 5.597; 95% confidence interval, 1.590-26.457; = 0.01; multivariable: odds ratio, 6.572; 95% confidence interval, 1.495-39.702; = 0.02) and of insufficient treatment response (univariate: odds ratio, 4.800; 95% confidence interval, 1.622-16.442; = 0.007; multivariable: odds ratio, 6.441; 95% confidence interval, 1.749-29.357; = 0.009). In a combined approach analysis, patients with levels above median cohort serum neurofilament light chain level reported strongly increased odds of demonstrating 1-year disease progression and/or therapy non-response during follow-up (univariate: odds ratio, 6.337; 95% confidence interval, 2.276-19.469; < 0.001; multivariable: odds ratio, 10.138; 95% confidence interval, 2.801-46.404;   0.001). These results show that in various logistic regression models, serum neurofilament light chain was associated with both 1-year disease progression and therapy response during follow-up in chronic inflammatory demyelinating polyneuropathy. Hence, our findings warrant further prospective research regarding the value of neurofilament light chain as potential prognostic biomarker in chronic inflammatory demyelinating polyneuropathy.
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http://dx.doi.org/10.1093/braincomms/fcab018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7991223PMC
March 2021

HDAC6 inhibition restores TDP-43 pathology and axonal transport defects in human motor neurons with TARDBP mutations.

EMBO J 2021 Apr 10;40(7):e106177. Epub 2021 Mar 10.

Department of Neurosciences, Experimental Neurology, Leuven Brain Institute (LBI), KU Leuven - University of Leuven, Leuven, Belgium.

TDP-43 is the major component of pathological inclusions in most ALS patients and in up to 50% of patients with frontotemporal dementia (FTD). Heterozygous missense mutations in TARDBP, the gene encoding TDP-43, are one of the common causes of familial ALS. In this study, we investigate TDP-43 protein behavior in induced pluripotent stem cell (iPSC)-derived motor neurons from three ALS patients with different TARDBP mutations, three healthy controls and an isogenic control. TARDPB mutations induce several TDP-43 changes in spinal motor neurons, including cytoplasmic mislocalization and accumulation of insoluble TDP-43, C-terminal fragments, and phospho-TDP-43. By generating iPSC lines with allele-specific tagging of TDP-43, we find that mutant TDP-43 initiates the observed disease phenotypes and has an altered interactome as indicated by mass spectrometry. Our findings also indicate that TDP-43 proteinopathy results in a defect in mitochondrial transport. Lastly, we show that pharmacological inhibition of histone deacetylase 6 (HDAC6) restores the observed TDP-43 pathologies and the axonal mitochondrial motility, suggesting that HDAC6 inhibition may be an interesting therapeutic target for neurodegenerative disorders linked to TDP-43 pathology.
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http://dx.doi.org/10.15252/embj.2020106177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8013789PMC
April 2021

Neuropathy of the phrenic nerve associated with antiganglioside antibodies.

Eur J Neurol 2021 06;28(6):2138-2141

Department of Neurology, University Hospitals Leuven, Leuven, Belgium.

Background And Purpose: Antiganglioside antibodies have been implicated in several autoimmune-mediated neuropathies, and binding of these antibodies can result in inflammatory changes of the nerves. Diaphragmatic paralysis is a rare condition, mostly arising from diseases affecting the phrenic nerve, neuromuscular junction, or skeletal muscle.

Objectives: In this case series, we identified five patients with diaphragmatic paralysis due to unilateral or bilateral neuropathy of the phrenic nerve associated with the presence of antiganglioside antibodies (immunoglobulin G anti-GT1a antibodies and immunoglobulin M anti-GM1 antibodies).

Discussion: The combination of an isolated phrenic nerve palsy with anti-GM1 antibodies has only once been described. On the other hand, the association of anti-GT1a antibodies with phrenic nerve palsy has never been reported before.

Conclusions: We report an association between phrenic nerve palsy and the presence of antiganglioside antibodies, but it remains unclear if there is a causal relationship. Further studies are needed to explore this matter.
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http://dx.doi.org/10.1111/ene.14814DOI Listing
June 2021

Quantitative Nucleocytoplasmic Transport Assays in Cellular Models of Neurodegeneration.

Bio Protoc 2020 Jun 20;10(12):e3659. Epub 2020 Jun 20.

Department of Microbiology, Immunology and Transplantation - Laboratory of Virology and Chemotherapy, KU Leuven - Rega Institute for Medical Research, Leuven, Belgium.

Nucleocytoplasmic transport deficits are suggested to play a role in neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). Given the importance and complexity of this process, understanding when these aberrations occur and which pathways are involved is of great importance. Here, we make use of CRISPR-Cas9 technology to design cell lines stably expressing fluorophore proteins shuttling between the nucleus and cytoplasm by karyopherins of choice. To validate this protocol, we measured an ALS-associated nucleocytoplasmic transport pathway in the presence of the disease-associated peptide poly-PR. This technique allows measuring a particular active nucleocytoplasmic transport pathway in intact cells in a neurodegenerative disease-associated context. Moreover, these experiments can be performed without the need for expensive equipment and have the potential to be upscaled for high-throughput screening purposes.
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http://dx.doi.org/10.21769/BioProtoc.3659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7842572PMC
June 2020

C9orf72 ALS-FTD: recent evidence for dysregulation of the autophagy-lysosome pathway at multiple levels.

Autophagy 2021 Feb 26:1-17. Epub 2021 Feb 26.

Department of Neurosciences, Experimental Neurology, and Leuven Brain Institute (LBI), KU Leuven-University of Leuven, Leuven, Belgium.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two clinically distinct classes of neurodegenerative disorders. Yet, they share a range of genetic, cellular, and molecular features. Hexanucleotide repeat expansions (HREs) in the gene and the accumulation of toxic protein aggregates in the nervous systems of the affected individuals are among such common features. Though the mechanisms by which HREs cause toxicity is not clear, the toxic gain of function due to transcribed HRE RNA or dipeptide repeat proteins (DPRs) produced by repeat-associated non-AUG translation together with a reduction in C9orf72 expression are proposed as the contributing factors for disease pathogenesis in ALS and FTD. In addition, several recent studies point toward alterations in protein homeostasis as one of the root causes of the disease pathogenesis. In this review, we discuss the effects of the C9orf72 HRE in the autophagy-lysosome pathway based on various recent findings. We suggest that dysfunction of the autophagy-lysosome pathway synergizes with toxicity from C9orf72 repeat RNA and DPRs to drive disease pathogenesis. ALP: autophagy-lysosome pathway; ALS: amyotrophic lateral sclerosis; AMPK: AMP-activated protein kinase; ATG: autophagy-related; ASO: antisense oligonucleotide; C9orf72: C9orf72-SMCR8 complex subunit; DENN: differentially expressed in normal and neoplastic cells; DPR: dipeptide repeat protein; EIF2A/eIF2α: eukaryotic translation initiation factor 2A; ER: endoplasmic reticulum; FTD: frontotemporal dementia; GAP: GTPase-activating protein; GEF: guanine nucleotide exchange factor; HRE: hexanucleotide repeat expansion; iPSC: induced pluripotent stem cell; ISR: integrated stress response; M6PR: mannose-6-phosphate receptor, cation dependent; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MN: motor neuron; MTORC1: mechanistic target of rapamycin kinase complex 1; ND: neurodegenerative disorder; RAN: repeat-associated non-ATG; RB1CC1/FIP200: RB1 inducible coiled-coil 1; SLC66A1/PQLC2: solute carrier family 66 member 1; SMCR8: SMCR8-C9orf72 complex subunit; SQSTM1/p62: sequestosome 1; STX17: syntaxin 17; TARDBP/TDP-43: TAR DNA binding protein; TBK1: TANK binding kinase 1; TFEB: transcription factor EB; ULK1: unc-51 like autophagy activating kinase 1; UPS: ubiquitin-proteasome system; WDR41: WD repeat domain 41.
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http://dx.doi.org/10.1080/15548627.2021.1872189DOI Listing
February 2021

STING-Induced Inflammation - A Novel Therapeutic Target in ALS?

N Engl J Med 2021 Feb;384(8):765-767

From VIB, Center for Brain and Disease Research, Laboratory of Neurobiology (P.V.D.), the Department of Neurosciences, Experimental Neurology, and Leuven Brain Institute, KU Leuven-University of Leuven, and the Department of Neurology, University Hospitals Leuven (P.V.D., W.R.), Leuven, Belgium.

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http://dx.doi.org/10.1056/NEJMcibr2031048DOI Listing
February 2021

AAV9-mediated gene delivery of MCT1 to oligodendrocytes does not provide a therapeutic benefit in a mouse model of ALS.

Mol Ther Methods Clin Dev 2021 Mar 20;20:508-519. Epub 2021 Jan 20.

Department of Neurosciences, Experimental Neurology and Leuven Brain Institute (LBI), KU Leuven - University of Leuven, Leuven, Belgium.

Oligodendrocyte dysfunction has been implicated in the pathophysiology of amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder characterized by progressive motor neuron loss. The failure of trophic support provided by oligodendrocytes is associated with a concomitant reduction in oligodendroglial monocarboxylate transporter 1 (MCT1) expression and is detrimental for the long-term survival of motor neuron axons. Therefore, we established an adeno-associated virus 9 (AAV9)-based platform by which MCT1 was targeted mostly to white matter oligodendrocytes to investigate whether this approach could provide a therapeutic benefit in the SOD1 mouse model of ALS. Despite good oligodendrocyte transduction and AAV-mediated MCT1 transgene expression, the disease outcome of SOD1 mice was not altered. Our study further increases our current understanding about the complex nature of oligodendrocyte pathology in ALS and provides valuable insights into the future development of therapeutic strategies to efficiently modulate these cells.
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http://dx.doi.org/10.1016/j.omtm.2021.01.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878966PMC
March 2021

Chitotriosidase as biomarker for early stage amyotrophic lateral sclerosis: a multicenter study.

Amyotroph Lateral Scler Frontotemporal Degener 2021 05 12;22(3-4):276-286. Epub 2021 Feb 12.

Department of Neurology, Ulm University, Ulm, Germany.

Levels of chitotriosidase (CHIT1) are increased in the cerebrospinal fluid (CSF) of amyotrophic lateral sclerosis (ALS) patients reflecting microglial activation. Here, we determine the diagnostic and prognostic potential of CHIT1 for early symptomatic ALS. : Overall, 275 patients from 8 European neurological centers were examined. We included ALS with <6 and >6 months from symptom onset, other motoneuron diseases (oMND), ALS mimics (DCon) and non-neurodegenerative controls (Con). CSF CHIT1 levels were analyzed for diagnostic power and association with progression and survival in comparison to the benchmark neurofilament. The 24-bp duplication polymorphism of CHIT1 was analyzed in a subset of patients ( = 65). Homozygous CHIT1 duplication mutation carriers (9%) invariably had undetectable CSF CHIT1 levels, while heterozygous carriers had similar levels as patients with wildtype CHIT1 ( = 0.414). In both early and late symptomatic ALS CHIT1 levels was increased, did not correlate with patients' progression rates, and was higher in patients diagnosed with higher diagnostic certainty. Neurofilament levels correlated with CHIT1 levels and prevailed over CHIT1 regarding diagnostic performance. Both CHIT1 and neurofilaments were identified as independent predictors of survival in late but not early symptomatic ALS. Evidence is provided that CHIT1 predicts progression in El Escorial diagnostic category in the group of ALS cases with a short duration. : CSF CHIT1 level may have additional value in the prognostication of ALS patients with a short history of symptoms classified in diagnostic categories of lower clinical certainty. To fully interpret apparently low CHIT1 levels knowledge of CHIT1 genotype is needed.
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http://dx.doi.org/10.1080/21678421.2020.1861023DOI Listing
May 2021

The Effect of SMN Gene Dosage on ALS Risk and Disease Severity.

Ann Neurol 2021 04 15;89(4):686-697. Epub 2021 Jan 15.

Department of Neurology, University of Massachusetts Medical School, Worcester, MA.

Objective: The role of the survival of motor neuron (SMN) gene in amyotrophic lateral sclerosis (ALS) is unclear, with several conflicting reports. A decisive result on this topic is needed, given that treatment options are available now for SMN deficiency.

Methods: In this largest multicenter case control study to evaluate the effect of SMN1 and SMN2 copy numbers in ALS, we used whole genome sequencing data from Project MinE data freeze 2. SMN copy numbers of 6,375 patients with ALS and 2,412 controls were called from whole genome sequencing data, and the reliability of the calls was tested with multiplex ligation-dependent probe amplification data.

Results: The copy number distribution of SMN1 and SMN2 between cases and controls did not show any statistical differences (binomial multivariate logistic regression SMN1 p = 0.54 and SMN2 p = 0.49). In addition, the copy number of SMN did not associate with patient survival (Royston-Parmar; SMN1 p = 0.78 and SMN2 p = 0.23) or age at onset (Royston-Parmar; SMN1 p = 0.75 and SMN2 p = 0.63).

Interpretation: In our well-powered study, there was no association of SMN1 or SMN2 copy numbers with the risk of ALS or ALS disease severity. This suggests that changing SMN protein levels in the physiological range may not modify ALS disease course. This is an important finding in the light of emerging therapies targeted at SMN deficiencies. ANN NEUROL 2021;89:686-697.
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http://dx.doi.org/10.1002/ana.26009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048961PMC
April 2021

TDP-43 proteinopathies: a new wave of neurodegenerative diseases.

J Neurol Neurosurg Psychiatry 2020 11 11. Epub 2020 Nov 11.

Westmead Clinical School, University of Sydney, Sydney, New South Wales, Australia

Inclusions of pathogenic deposits containing TAR DNA-binding protein 43 (TDP-43) are evident in the brain and spinal cord of patients that present across a spectrum of neurodegenerative diseases. For instance, the majority of patients with sporadic amyotrophic lateral sclerosis (up to 97%) and a substantial proportion of patients with frontotemporal lobar degeneration (~45%) exhibit TDP-43 positive neuronal inclusions, suggesting a role for this protein in disease pathogenesis. In addition, TDP-43 inclusions are evident in familial ALS phenotypes linked to multiple gene mutations including the TDP-43 gene coding () and unrelated genes (eg, ). While TDP-43 is an essential RNA/DNA binding protein critical for RNA-related metabolism, determining the pathophysiological mechanisms through which TDP-43 mediates neurodegeneration appears complex, and unravelling these molecular processes seems critical for the development of effective therapies. This review highlights the key physiological functions of the TDP-43 protein, while considering an expanding spectrum of neurodegenerative diseases associated with pathogenic TDP-43 deposition, and dissecting key molecular pathways through which TDP-43 may mediate neurodegeneration.
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http://dx.doi.org/10.1136/jnnp-2020-322983DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803890PMC
November 2020

Brain metabolic changes across King's stages in amyotrophic lateral sclerosis: a F-2-fluoro-2-deoxy-D-glucose-positron emission tomography study.

Eur J Nucl Med Mol Imaging 2021 04 7;48(4):1124-1133. Epub 2020 Oct 7.

ALS Centre, "Rita Levi Montalcini" Department of Neuroscience, University of Turin, Via Cherasco 15, 10126, Turin, Italy.

Purpose: To assess the brain metabolic correlates of the different regional extent of ALS, evaluated with the King's staging system, using brain F-2-fluoro-2-deoxy-D-glucose-PET (F-FDG-PET).

Methods: Three hundred ninety ALS cases with King's stages 1, 2, and 3 (n = 390), i.e., involvement of 1, 2, and 3 body regions respectively, underwent brain F-FDG-PET at diagnosis. King's stage at PET was derived from ALSFRS-R and was regressed out against whole-brain metabolism in the whole sample. The full factorial design confirmed the hypothesis that differences among groups (King's 1, King's 2, King's 3, and 40 healthy controls (HC)) existed overall. Comparisons among stages and between each group and HC were performed. We included age at PET and sex as covariates.

Results: Brain metabolism was inversely correlated with stage in medial frontal gyrus bilaterally, and right precentral and postcentral gyri. The full factorial design resulted in a significant main effect of groups. There was no significant difference between stages 1 and 2. Comparing stage 3 to stage 1+2, a significant relative hypometabolism was highlighted in the former in the left precentral and medial frontal gyri, and in the right medial frontal, postcentral, precentral, and middle frontal gyri. The comparisons between each group and HC showed the extension of frontal metabolic changes from stage 1 to stage 3, with the larger metabolic gap between stages 2 and 3.

Conclusions: Our findings support the hypothesis that in ALS, the propagation of neurodegeneration follows a corticofugal, regional ordered pattern, extending from the motor cortex to posterior and anterior regions.
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http://dx.doi.org/10.1007/s00259-020-05053-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8041703PMC
April 2021

repeat expansions confer risk for amyotrophic lateral sclerosis and contribute to TDP-43 mislocalization.

Brain Commun 2020 19;2(2):fcaa064. Epub 2020 May 19.

Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute and United Kingdom Dementia Research Institute, King's College London, London SE5 9NU, UK.

Increasingly, repeat expansions are being identified as part of the complex genetic architecture of amyotrophic lateral sclerosis. To date, several repeat expansions have been genetically associated with the disease: intronic repeat expansions in , polyglutamine expansions in and polyalanine expansions in . Together with previously published data, the identification of an amyotrophic lateral sclerosis patient with a family history of spinocerebellar ataxia type 1, caused by polyglutamine expansions in , suggested a similar disease association for the repeat expansion in . We, therefore, performed a large-scale international study in 11 700 individuals, in which we showed a significant association between intermediate repeat expansions and amyotrophic lateral sclerosis (=3.33 × 10). Subsequent functional experiments have shown that ATXN1 reduces the nucleocytoplasmic ratio of TDP-43 and enhances amyotrophic lateral sclerosis phenotypes in , further emphasizing the role of polyglutamine repeat expansions in the pathophysiology of amyotrophic lateral sclerosis.
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http://dx.doi.org/10.1093/braincomms/fcaa064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425293PMC
May 2020

Dipeptide repeat protein and TDP-43 pathology along the hypothalamic-pituitary axis in C9orf72 and non-C9orf72 ALS and FTLD-TDP cases.

Acta Neuropathol 2020 11 30;140(5):777-781. Epub 2020 Aug 30.

Laboratory for Neuropathology, Department of Imaging and Pathology, Leuven Brain Institute (LBI), KU Leuven (University of Leuven), O&N IV Herestraat 49-Bus 1032, 3000, Leuven, Belgium.

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http://dx.doi.org/10.1007/s00401-020-02216-9DOI Listing
November 2020

Diagnostic yield of testing for repeat expansions in patients with unexplained adult-onset cerebellar ataxia.

J Neurol Neurosurg Psychiatry 2020 11 30;91(11):1233-1234. Epub 2020 Jul 30.

Department of Neurology, University Hospitals Leuven, Leuven, Flanders, Belgium

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http://dx.doi.org/10.1136/jnnp-2020-323998DOI Listing
November 2020

Non-invasive characterization of amyotrophic lateral sclerosis in a hTDP-43 mouse model: A PET-MR study.

Neuroimage Clin 2020 25;27:102327. Epub 2020 Jun 25.

Biomedical MRI Unit/MoSAIC, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium.

Currently TAR DNA binding protein 43 (TDP-43) pathology, underlying Amyotrophic Lateral Sclerosis (ALS), remains poorly understood which hinders both clinical diagnosis and drug discovery efforts. To better comprehend the disease pathophysiology, positron emission tomography (PET) and multi-parametric magnetic resonance imaging (mp-MRI) provide a non-invasive mode to investigate molecular, structural, and neurochemical abnormalities in vivo. For the first time, we report the findings of a longitudinal PET-MR study in the TDP-43 ALS mouse model, investigating disease-related changes in the mouse brain. 2-deoxy-2-[F]fluoro-D-glucose [F]FDG PET showed significantly lowered glucose metabolism in the motor and somatosensory cortices of TDP-43 mice whereas metabolism was elevated in the region covering the bilateral substantia nigra, reticular and amygdaloid nucleus between 3 and 7 months of age, as compared to non-transgenic controls. MR spectroscopy data showed significant changes in glutamate + glutamine (Glx) and choline levels in the motor cortex and hindbrain of TDP-43 mice compared to controls. Cerebral blood flow (CBF) measurements, using an arterial spin labelling approach, showed no significant age- or group-dependent changes in brain perfusion. Diffusion MRI indices demonstrated transient changes in different motor areas of the brain in TDP-43 mice around 14 months of age. Cytoplasmic TDP-43 proteinaceous inclusions were observed in the brains of symptomatic, 18-month-old mice, but not in non-symptomatic transgenic or wild-type mice. Our results reveal that disease- and age-related functional and neurochemical alterations, together with limited structural changes, occur in specific brain regions of transgenic TDP-43 mice, as compared to their healthy counterparts. Altogether these findings shed new light on TDP-43 disease pathogenesis and may prove useful for clinical management of ALS.
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http://dx.doi.org/10.1016/j.nicl.2020.102327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352080PMC
June 2021

TRICALS: creating a highway toward a cure.

Amyotroph Lateral Scler Frontotemporal Degener 2020 11 9;21(7-8):496-501. Epub 2020 Jul 9.

Department of Neurology, UMC Utrecht Brain Centre, University Medical Centre Utrecht, Utrecht, the Netherlands.

A change in our current approach toward drug development is required to improve the likelihood of finding effective treatment for patients with amyotrophic lateral sclerosis (ALS). The aim of the Treatment Research Initiative to Cure ALS (TRICALS) is to extend the collective effort with industry and consolidate drug development paths. TRICALS has begun a series of meetings on how to best move the field forward collaboratively, thereby addressing five major topics in ALS clinical trials: (1) preclinical research, (2) biomarker development, (3) eligibility criteria, (4) efficacy endpoints and (5) innovative trial design. There is an appetite for ongoing discussions of these major topics in clinical trials between representatives from academia, patient advocacy groups, industry partners and funding bodies. Industry is open to fundamentally change drug development for ALS and shorten the time to effective therapy for patients by implementing promising innovations in biomarker development, trial design, and patient selection. There is however, a pressing need from all stakeholders for regulatory discussions and amendments of current guidelines to successfully adopt innovation in future clinical development lines.
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http://dx.doi.org/10.1080/21678421.2020.1788092DOI Listing
November 2020

Phase 1-2 Trial of Antisense Oligonucleotide Tofersen for ALS.

N Engl J Med 2020 07;383(2):109-119

From the Washington University School of Medicine, St. Louis (T.M., R.C.B., A.P.); the Healey Center for ALS, Massachusetts General Hospital, Harvard Medical School, Boston (M.C., N.A.), and Biogen, Cambridge (A.S., H.R., D.G., H.H., A.M., I.N., I.C., L.F., S.F., T.A.F.) - both in Massachusetts; the Sheffield Institute for Translational Neuroscience, University of Sheffield, and NIHR Sheffield Biomedical Research Centre and Clinical Research Facility, University of Sheffield and Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield (P.J.S., C.J.M.), and Biogen, Maidenhead (M.M.) - both in the United Kingdom; the Department of Clinical Science, Neurosciences, Umeå University, Umea, Sweden (P.M.A.); Montreal Neurological Institute and Hospital, Montreal (A.G.), and Sunnybrook Research Institute, Toronto (L.Z.); Emory University, Atlanta (J.G.); Barrow Neurological Institute, Phoenix, AZ (S.L.); the University of Ulm, Ulm, Germany (A.L.L.); Johns Hopkins University School of Medicine, Baltimore (N.J.M.); the University of California San Diego, La Jolla (J.R.), and Ionis Pharmaceuticals, Carlsbad (C.F.B., R.L.) - both in California; Paris ALS Centre, Hôpital de la Salpêtrière, Paris (F.S.); the University of Tennessee Medical Center, Knoxville (R.T.); and KU Leuven, VIB Center for Brain and Disease Research, University Hospitals Leuven, Leuven, Belgium (P.V.D.).

Background: Tofersen is an antisense oligonucleotide that mediates the degradation of superoxide dismutase 1 (SOD1) messenger RNA to reduce SOD1 protein synthesis. Intrathecal administration of tofersen is being studied for the treatment of amyotrophic lateral sclerosis (ALS) due to mutations.

Methods: We conducted a phase 1-2 ascending-dose trial evaluating tofersen in adults with ALS due to mutations. In each dose cohort (20, 40, 60, or 100 mg), participants were randomly assigned in a 3:1 ratio to receive five doses of tofersen or placebo, administered intrathecally for 12 weeks. The primary outcomes were safety and pharmacokinetics. The secondary outcome was the change from baseline in the cerebrospinal fluid (CSF) SOD1 concentration at day 85. Clinical function and vital capacity were measured.

Results: A total of 50 participants underwent randomization and were included in the analyses; 48 participants received all five planned doses. Lumbar puncture-related adverse events were observed in most participants. Elevations in CSF white-cell count and protein were reported as adverse events in 4 and 5 participants, respectively, who received tofersen. Among participants who received tofersen, one died from pulmonary embolus on day 137, and one from respiratory failure on day 152; one participant in the placebo group died from respiratory failure on day 52. The difference at day 85 in the change from baseline in the CSF SOD1 concentration between the tofersen groups and the placebo group was 2 percentage points (95% confidence interval [CI], -18 to 27) for the 20-mg dose, -25 percentage points (95% CI, -40 to -5) for the 40-mg dose, -19 percentage points (95% CI, -35 to 2) for the 60-mg dose, and -33 percentage points (95% CI, -47 to -16) for the 100-mg dose.

Conclusions: In adults with ALS due to mutations, CSF SOD1 concentrations decreased at the highest concentration of tofersen administered intrathecally over a period of 12 weeks. CSF pleocytosis occurred in some participants receiving tofersen. Lumbar puncture-related adverse events were observed in most participants. (Funded by Biogen; ClinicalTrials.gov number, NCT02623699; EudraCT number, 2015-004098-33.).
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http://dx.doi.org/10.1056/NEJMoa2003715DOI Listing
July 2020
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