The DOI matches its Crossref record; 27 of the 27 references it cites were found in a registry or an index.
Phase 1–2 Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS
Open accessAbstract
BACKGROUND: mutations. METHODS: 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: 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.).
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The cited source says what the claim attributes to it.
In the citing paper
“ASO injection is a current standard of care for the fatal childhood disease spinal muscular atrophy15 and is in five ongoing Phase I trials in ALS, Parkinson’s, and Alzheimer’s diseases and in Phase III trials for inherited ALS from a mutation in superoxide dismutase16,17 and for Huntington’s disease18.”
From Therapeutically viable generation of neurons with antisense oligonucleotide suppression of PTB (2021) · cites this paper as [17]
The check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“Experience from Alzheimer’s disease (AD), spinal muscular atrophy (SMA),5 and amyotrophic lateral sclerosis (ALS)6 suggests treating FTD will be most successful if treatment is initiated early in the disease course, ideally prior to the onset of symptoms.”
From Temporal order of clinical and biomarker changes in familial frontotemporal dementia (2022) · cites this paper as [6]
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy
Finkel, R. S., Mercuri, E., Darras, B. T., Connolly, A. M., Kuntz, N. L., Kirschner, J., Chiriboga, C. A., Saito, K., Servais, L., Tizzano, E., et al. (2017) · New England Journal of Medicine · doi:10.1056/nejmoa1702752 · Cited by 2,337
Self-citationNusinersen versus Sham Control in Later-Onset Spinal Muscular Atrophy
Mercuri, E., Darras, B. T., Chiriboga, C. A., Day, J. W., Campbell, C., Connolly, A. M., Iannaccone, S. T., Kirschner, J., Kuntz, N. L., Saito, K., et al. (2018) · New England Journal of Medicine · doi:10.1056/nejmoa1710504 · Cited by 1,433
Self-citationNon–cell autonomous toxicity in neurodegenerative disorders: ALS and beyond
Ilieva, H., Polymenidou, M., & Cleveland, D. W. (2009) · Journal of Cell Biology · doi:10.1083/jcb.200908164 · Cited by 1,008
Antisense oligonucleotides: the next frontier for treatment of neurological disorders
Rinaldi, C., & Wood, M. J. A. (2018) · Nature Reviews Neurology · doi:10.1038/nrneurol.2017.148 · Cited by 788
Epidemiology of mutations in superoxide dismutase in amyotrophic lateal sclerosis
Cudkowicz, M., McKenna‐Yasek, D., Sapp, P. C., Chin, W., Geller, B. A., Hayden, D. L., Schoenfeld, D., Hosler, B. A., Horvitz, H. R., & Brown, R. H. (1997) · Annals of Neurology · doi:10.1002/ana.410410212 · Cited by 533
Self-citationAntisense oligonucleotide therapy for neurodegenerative disease
Smith, R. A. (2006) · Journal of Clinical Investigation · doi:10.1172/jci25424 · Cited by 506
ALSoD: A user-friendly online bioinformatics tool for amyotrophic lateral sclerosis genetics
Abel, O., Powell, J. F., Andersen, P. M., & Al‐Chalabi, A. (2012) · Human Mutation · doi:10.1002/humu.22157 · Cited by 341
Self-citationIs SOD1 loss of function involved in amyotrophic lateral sclerosis?
Saccon, R. A., Bunton-Stasyshyn, R. K. A., Fisher, E., & Fratta, P. (2013) · Brain · doi:10.1093/brain/awt097 · Cited by 339
Andersen, P. M., Nilsson, P., Ala‐Hurula, V., Keränen, M.-L., Tarvainen, I., Haltia, T., Nilsson, L., Binzer, M., Forsgren, L., & Marklund, S. L. (1995) · Nature Genetics · doi:10.1038/ng0595-61 · Cited by 323
Self-citationAndersen, P. M. (1997) · Brain · doi:10.1093/brain/120.10.1723 · Cited by 301
Self-citation
Cited by
Sorted by citations
Feldman, E. L., Goutman, S. A., Petri, S., Mazzini, L., Savelieff, M. G., Shaw, P. J., & Sobue, G. (2022) · The Lancet · doi:10.1016/s0140-6736(22)01272-7 · Cited by 1,267
Self-citationTrial of Antisense Oligonucleotide Tofersen for SOD1 ALS
Miller, T. M., Cudkowicz, M. E., Genge, A., Shaw, P. J., Sobue, G., Bucelli, R. C., Chiò, A., Van Damme, P., Ludolph, A. C., Glass, J. D., et al. (2022) · New England Journal of Medicine · doi:10.1056/nejmoa2204705 · Cited by 966
Self-citationAntisense technology: an overview and prospectus
Crooke, S. T., Baker, B. F., Crooke, R. M., & Liang, X.-H. (2021) · Nature Reviews Drug Discovery · doi:10.1038/s41573-021-00162-z · Cited by 775
Mead, R. J., Shan, N., Reiser, H. J., Marshall, F., & Shaw, P. J. (2023) · Nature Reviews Drug Discovery · doi:10.1038/s41573-022-00612-2 · Cited by 505
Self-citationNeurofilaments as biomarkers in neurological disorders — towards clinical application
Khalil, M., Teunissen, C. E., Lehmann, S., Otto, M., Piehl, F., Ziemssen, T., Bittner, S., Sormani, M. P., Gattringer, T., Abu‐Rumeileh, S., et al. (2024) · Nature Reviews Neurology · doi:10.1038/s41582-024-00955-x · Cited by 503
Emerging insights into the complex genetics and pathophysiology of amyotrophic lateral sclerosis
Goutman, S. A., Hardiman, O. M., Al‐Chalabi, A., Chiò, A., Savelieff, M. G., Kiernan, M. C., & Feldman, E. L. (2022) · The Lancet Neurology · doi:10.1016/s1474-4422(21)00414-2 · Cited by 432
ALS Genetics: Gains, Losses, and Implications for Future Therapies
Kim, G., Gautier, O., Tassoni-Tsuchida, E., Ma, X. R., & Gitler, A. D. (2020) · Neuron · doi:10.1016/j.neuron.2020.08.022 · Cited by 370
“The treated group also showed better performance in two other clinical measures—slow vital capacity and handheld dynamometry—compared to the placebo group (Miller et al., 2020).”
BackgroundInfluentialMummery, C. J., Börjesson-Hanson, A., Blackburn, D. J., Vijverberg, E. G. B., De Deyn, P. P., Ducharme, S., Jonsson, M., Schneider, A., Rinne, J. O., Ludolph, A. C., et al. (2023) · Nature Medicine · doi:10.1038/s41591-023-02326-3 · Cited by 347
“It is not feasible to directly quantify the reduction of MAPT mRNA or tau protein in cortical tissue in a clinical trial; however, it is possible to index PD activity with CSF protein assays 31,32 .”
Self-citationTabrizi, S. J., Estevez‐Fraga, C., van Roon‐Mom, W., Flower, M. D., Scahill, R. I., Wild, E. J., Muñoz-Sanjuán, I., Sampaio, C., Rosser, A., & Leavitt, B. R. (2022) · The Lancet Neurology · doi:10.1016/s1474-4422(22)00121-1 · Cited by 354
Antisense technology: A review
Crooke, S. T., Liang, X., Baker, B. F., & Crooke, R. M. (2021) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2021.100416 · Cited by 350
“This is an open access article under the CC Table 1 Clinical development activities of antisense medicines A - approved RNA targeted drugs Drug Indication Target RNA Mechanism Chemistry Year approved Fomivirsen Cytomegalovirus retinitis HCMV UL122 RNase H1 PS, DNA 1998 Mipomersen Homozygous familial hypercholesterolem…”
BackgroundA Decade of FDA-Approved Drugs (2010–2019): Trends and Future Directions
Brown, D. G., & Wobst, H. J. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c01516 · Cited by 338
Blood neurofilament light: a critical review of its application to neurologic disease
Barro, C., Chitnis, T., & Weiner, H. L. (2020) · Annals of Clinical and Translational Neurology · doi:10.1002/acn3.51234 · Cited by 296
“A phase 1-2 clinical trial that explored the safety of Tofersen, a treatment based on antisense oligonucleotides targeting SOD1 messenger RNA, resulted in not only a decrease in CSF SOD1 levels but also a decrease in both NfL and pNfH levels whereas levels in the placebo arm remained stable.(110) Affected neurons in A…”
BackgroundImproving clinical trial outcomes in amyotrophic lateral sclerosis
Kiernan, M. C., Vucic, S., Talbot, K., McDermott, C. J., Hardiman, O. M., Shefner, J. M., Al‐Chalabi, A., Huynh, W., Cudkowicz, M., Talman, P. S., et al. (2020) · Nature Reviews Neurology · doi:10.1038/s41582-020-00434-z · Cited by 306
Self-citationNeurofilament Proteins as Biomarkers to Monitor Neurological Diseases and the Efficacy of Therapies
Yuan, A., & Nixon, R. A. (2021) · Frontiers in Neuroscience · doi:10.3389/fnins.2021.689938 · Cited by 304
SOD1 Suppression with Adeno-Associated Virus and MicroRNA in Familial ALS
Mueller, C., Berry, J. D., McKenna-Yasek, D. M., Gernoux, G., Owegi, M. A., Pothier, L. M., Douthwright, C. L., Gelevski, D., Luppino, S. D., Blackwood, M., et al. (2020) · New England Journal of Medicine · doi:10.1056/nejmoa2005056 · Cited by 264
Self-citationRNA therapy: rich history, various applications and unlimited future prospects
Kim, Y. (2022) · Experimental & Molecular Medicine · doi:10.1038/s12276-022-00757-5 · Cited by 283
Superoxide Dismutase Administration: A Review of Proposed Human Uses
Rosa, A. C., Corsi, D., Cavi, N., Bruni, N., & Dosio, F. (2021) · Molecules · doi:10.3390/molecules26071844 · Cited by 297
Mechanism of STMN2 cryptic splice-polyadenylation and its correction for TDP-43 proteinopathies
Baughn, M. W., Melamed, Z., López‐Erauskin, J., Beccari, M. S., Ling, K., Zuberi, A. R., Presa, M. F., Gonzalo-Gil, E., Maimon, R., Vazquez‐Sanchez, S., et al. (2023) · Science · doi:10.1126/science.abq5622 · Cited by 252
Self-citationThe Challenges and Strategies of Antisense Oligonucleotide Drug Delivery
Gagliardi, M. E., & Ashizawa, A. T. (2021) · Biomedicines · doi:10.3390/biomedicines9040433 · Cited by 217
“This modification has been implemented for the improvement of a Superoxide Dismutase 1-targeting ASO currently in clinical trial for the treatment of amyotrophic lateral sclerosis [78,79].”
MethodiPSC-based disease modeling and drug discovery in cardinal neurodegenerative disorders
Okano, H., & Morimoto, S. (2022) · Cell stem cell · doi:10.1016/j.stem.2022.01.007 · Cited by 206
Gene therapy for ALS: A review
Amado, D. A., & Davidson, B. L. (2021) · Molecular Therapy · doi:10.1016/j.ymthe.2021.04.008 · Cited by 203
Gene-based therapies for neurodegenerative diseases
Sun, J., & Roy, S. (2021) · Nature Neuroscience · doi:10.1038/s41593-020-00778-1 · Cited by 194
Blair, H. A. (2023) · Drugs · doi:10.1007/s40265-023-01904-6 · Cited by 190
“Part A (single ascending dose [9]) and part B (multiple ascending dose [10]) were phase I/II dose-escalation trials conducted to assess the dose of tofersen to be used in part C, the 28-week, double-blind, randomized, placebo-controlled, phase III component of the trial.”
MethodBenatar, M. G., Wuu, J., Andersen, P. M., Bucelli, R. C., Andrews, J. A., Otto, M., Farahany, N. A., Harrington, E. A., Chen, W., Mitchell, A. A., et al. (2022) · Neurotherapeutics · doi:10.1007/s13311-022-01237-4 · Cited by 182
“In clinical studies (NCT02623699, NCT03070119) designed to evaluate tofersen in symptomatic patients with SOD1-ALS, intrathecal administration of tofersen 100 mg led to robust reductions in total cerebrospinal fluid (CSF) SOD1 protein, a marker of target engagement, and plasma NfL, a marker of neuronal degeneration [2…”
BackgroundSelf-citationLiu, M., Wang, Y., Zhang, Y.-B., Hu, D., Tang, L., Zhou, B., & Yang, L. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-02112-8 · Cited by 189
Baloh, R. H., Johnson, J. P., Avalos, P., Allred, P., Svendsen, S. P., Gowing, G., Roxas, K., Wu, A., Donahue, B., Osborne, S., et al. (2022) · Nature Medicine · doi:10.1038/s41591-022-01956-3 · Cited by 157
α-Synuclein antisense oligonucleotides as a disease-modifying therapy for Parkinson’s disease
Cole, T. A., Zhao, H. T., Collier, T. J., Sandoval, I. M., Sortwell, C. E., Steece‐Collier, K., Daley, B. F., Booms, A., Lipton, J. W., Welch, M., et al. (2021) · JCI Insight · doi:10.1172/jci.insight.135633 · Cited by 171
“To treat human patients, we designed ASOs to suppress the human SNCA transcript, using similar designs and chemistries as ASOs already in clinical testing (45, 46).”
MethodSelf-citationNeurofilament Light Chain as Biomarker for Amyotrophic Lateral Sclerosis and Frontotemporal Dementia
Verde, F., Otto, M., & Silani, V. (2021) · Frontiers in Neuroscience · doi:10.3389/fnins.2021.679199 · Cited by 160
“The highest dose of the drug administered intrathecally over a period of 12 weeks produced a significant decrease in CSF SOD1 concentrations; importantly, this was accompanied by a decrease of both CSF and plasma concentrations of NFL (and pNFH), representing one of the first examples of the use of neurofilaments as p…”
BackgroundCurrent State and Future Directions in the Therapy of ALS
Tzeplaeff, L., Wilfling, S., Requardt, M. V., & Herdick, M. L. (2023) · Cells · doi:10.3390/cells12111523 · Cited by 171
Temporal order of clinical and biomarker changes in familial frontotemporal dementia
Staffaroni, A. M., Quintana, M., Wendelberger, B., Heuer, H. W., Russell, L. L., Cobigo, Y., Wolf, A., Goh, S.-Y. M., Petrucelli, L., Gendron, T. F., et al. (2022) · Nature Medicine · doi:10.1038/s41591-022-01942-9 · Cited by 140
Minikel, E. V., Zhao, H. T., Le, J., O’Moore, J., Pitstick, R., Graffam, S., Carlson, G. A., Kavanaugh, M. P., Križ, J., Kim, J. B., et al. (2020) · Nucleic Acids Research · doi:10.1093/nar/gkaa616 · Cited by 144
“…additionally test the ASO chemistry now in clinical trials for Huntington’s disease and Amyotrophic lateral sclerosis (ALS) with SOD1 mutations (25,55), we undertook optimization at the binding sites of active ASOs 1 and 2 to design and synthesize a set of ASOs with mixed PS / PO backbones and a…”
Barker, S. J., Thayer, M. B., Kim, C., Tatarakis, D., Simon, M. J., Dial, R., Nilewski, L., Wells, R. C., Zhou, Y., Afetian, M., et al. (2024) · Science Translational Medicine · doi:10.1126/scitranslmed.adi2245 · Cited by 142
“…bio-distribution that results in reduced drug concentrations in deeper brain regions and increased concentrations in the lumbar spinal cord ( 12 ) as well as the potential for adverse events related to intra-thecal dosing that can lead to dose limitations or study discontinuation ( 6 , 13 ).”
BackgroundGenetics of amyotrophic lateral sclerosis: seeking therapeutic targets in the era of gene therapy
Suzuki, N., Nishiyama, A., Warita, H., & Aoki, M. (2022) · Journal of Human Genetics · doi:10.1038/s10038-022-01055-8 · Cited by 148
“Tofersen for superoxide dismutase 1 (SOD1) was a pioneer in developing ASO therapies for ALS [7]; however, it failed to show significant improvement in the primary endpoint in a phase 3 trial [8].”
BackgroundFluid biomarkers in frontotemporal dementia: past, present and future
Swift, I. J., Sogorb-Esteve, A., Heller, C., Synofzik, M., Otto, M., Graff, C., Galimberti, D., Todd, E., Heslegrave, A. J., van der Ende, E. L., et al. (2021) · Journal of Neurology, Neurosurgery & Psychiatry · doi:10.1136/jnnp-2020-323520 · Cited by 122
Jafar-nejad, P., Powers, B., Soriano, A., Zhao, H., Norris, D. A., Matson, J., DeBrosse-Serra, B., Watson, J., Narayanan, P., Chun, S. J., et al. (2021) · Nucleic Acids Research · doi:10.1093/nar/gkaa1235 · Cited by 128
“The Malat1 ASO is the standard 5–10–5 MOE-gapmer design that is frequently used in preclinical research (8,10,12–14,16–18) as well as in ongoing clinical trials (19,20).”
BackgroundMethodNucleic Acid Therapeutics: Successes, Milestones, and Upcoming Innovation
Belgrad, J., Fakih, H. H., & Khvorova, A. (2024) · Nucleic Acid Therapeutics · doi:10.1089/nat.2023.0068 · Cited by 130
Preventing amyotrophic lateral sclerosis: insights from pre-symptomatic neurodegenerative diseases
Benatar, M. G., Wuu, J., McHutchison, C. A., Postuma, R. B., Boeve, B. F., Petersen, R. C., Ross, C. A., Rosen, H. J., Arias, J. J., Fradette, S., et al. (2021) · Brain · doi:10.1093/brain/awab404 · Cited by 129
“In addition, intrathecally administered SOD1 antisense oligonucleotide is ready for investigation in this population given the emerging evidence for its safety and potential efficacy in the symptomatic SOD1 population.(135) In addition to advancing the understanding of pre-symptomatic ALS and phenoconversion among thi…”
Self-citationThe multifaceted role of neurofilament light chain protein in non-primary neurological diseases
Abu‐Rumeileh, S., Abdelhak, A., Foschi, M., D’Anna, L., Russo, M., Steinacker, P., Kühle, J., Tumani, H., Blennow, K., & Otto, M. (2022) · Brain · doi:10.1093/brain/awac328 · Cited by 124
Wiesenfarth, M., Dorst, J., Brenner, D., Elmas, Z. G., Parlak, Ö., Uzelac, Ž., Kandler, K., Mayer, K., Weiland, U., Herrmann, C. H., et al. (2024) · EClinicalMedicine · doi:10.1016/j.eclinm.2024.102495 · Cited by 122
“18,19 During the initial placebo-controlled phase I-III trial, a signi fi cant reduction of neuro fi lament light chain (NfL) in plasma compared to placebo suggested a disease-modifying effect, 19 although clinical progression parameters such as ALS functional rating scale revised (ALSFRS-R) did not…”
MethodSelf-citationAntisense drugs make sense for neurological diseases
Bennett, C. F., Kordasiewicz, H. B., & Cleveland, D. W. (2021) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-010919-023738 · Cited by 108
Self-citationNeurofilaments in motor neuron disorders: towards promising diagnostic and prognostic biomarkers
Zucchi, E., Bonetto, V., Sorarú, G., Martinelli, I., Parchi, P., Liguori, R., & Mandrioli, J. (2020) · Molecular Neurodegeneration · doi:10.1186/s13024-020-00406-3 · Cited by 112
Julian, T. H., Glascow, N., Barry, A. D. F., Moll, T., Harvey, C., Klimentidis, Y. C., Newell, M., Zhang, S., Snyder, M. P., Cooper‐Knock, J., et al. (2021) · EBioMedicine · doi:10.1016/j.ebiom.2021.103397 · Cited by 117
“For rare forms of ALS which are purely genetically determined, this is already a reality [54].”
BackgroundSelf-citationAdvances in molecular pathology, diagnosis, and treatment of amyotrophic lateral sclerosis
Ilieva, H., Vullaganti, M., & Kwan, J. (2023) · BMJ · doi:10.1136/bmj-2023-075037 · Cited by 111
Meyer, T., Schumann, P., Weydt, P., Petri, S., Koc, Y., Spittel, S., Bernsen, S., Günther, R., Weishaupt, J. H., Dreger, M., et al. (2023) · Muscle & Nerve · doi:10.1002/mus.27818 · Cited by 104
Giacomelli, E., Vahsen, B. F., Calder, E. L., Xu, Y., Scaber, J., Gray, E., Dafinca, R., Talbot, K., & Studer, L. (2022) · Cell stem cell · doi:10.1016/j.stem.2021.12.008 · Cited by 100
Antisense Oligonucleotides for the Study and Treatment of ALS
Boros, B. D., Schoch, K. M., Kreple, C. J., & Miller, T. M. (2022) · Neurotherapeutics · doi:10.1007/s13311-022-01247-2 · Cited by 114
“At study day 85, SOD1 was reduced in the 40 mg (27%), 60 mg (21%), and 100 mg (36%) groups, demonstrating effective target engagement [29].”
BackgroundMethodInfluentialSelf-citationHemerková, P., & Vališ, M. (2021) · Biomolecules · doi:10.3390/biom11030437 · Cited by 100
“The highest administered dose of the drug led to a reduction in the amount of mutated SOD in the cerebrospinal fluid and also to a decrease in the amount of neurofilaments, a marker of neuronal decay [220].”
BackgroundCrossing the blood–brain barrier: emerging therapeutic strategies for neurological disease
Pedder, J. H., Sonabend, A. M., Cearns, M. D., Michael, B. D., Zakaria, R., Heimberger, A. B., Jenkinson, M. D., & Dickens, D. (2025) · The Lancet Neurology · doi:10.1016/s1474-4422(24)00476-9 · Cited by 114
Recent progress of the genetics of amyotrophic lateral sclerosis and challenges of gene therapy
Wang, H., Guan, L., & Deng, M. (2023) · Frontiers in Neuroscience · doi:10.3389/fnins.2023.1170996 · Cited by 108
Pharmacotherapy for Amyotrophic Lateral Sclerosis: A Review of Approved and Upcoming Agents
Johnson, S. A., Fang, T., Marchi, F. D., Neel, D. V., Weehaeghe, D. V., Berry, J. D., & Paganoni, S. (2022) · Drugs · doi:10.1007/s40265-022-01769-1 · Cited by 105
“They were safe in a human Phase 1–2 trial [105].”
BackgroundHarnessing cerebrospinal fluid circulation for drug delivery to brain tissues
Naseri Kouzehgarani, G., Feldsien, T., Engelhard, H. H., Mirakhur, K. K., Phipps, C., Nimmrich, V., Clausznitzer, D., & Lefebvre, D. R. (2021) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2021.03.002 · Cited by 95
Targeted gene silencing in the nervous system with CRISPR-Cas13
Powell, J. E., Lim, C. K. W., Krishnan, R. S. G., McCallister, T. X., Saporito-Magriñá, C., C., M. A. Z., McPheron, G. D., & Gaj, T. (2022) · Science Advances · doi:10.1126/sciadv.abk2485 · Cited by 96
“While, to date, non–allele-specific targeting for SOD1linked ALS has resulted in no serious side effects and produced evidence of clinical improvement (19), a phase 3 clinical trial designed to evaluate the effectiveness of an intrathecally administered non–allele-specific ASO for HD was recently halted following a re…”
BackgroundInfluentialCombating deleterious phase transitions in neurodegenerative disease
Darling, A. L., & Shorter, J. (2021) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2021.118984 · Cited by 88
“Moreover, in a transgenic ALS SOD1-G93A mouse model, there was a robust increase of HspB8 protein levels in the anterior horn cells of the spinal cord that survived to end-stage of disease [232].”
BackgroundInfluentialClinical trials in amyotrophic lateral sclerosis: a systematic review and perspective
Wong, C., Stavrou, M., Elliott, E., Gregory, J. M., Leigh, N. P., Pinto, A. A., Williams, T. L., Chataway, J., Swingler, R. J., Parmar, M., et al. (2021) · Brain Communications · doi:10.1093/braincomms/fcab242 · Cited by 86
“Moreover, the emergence of gene-based treatment approaches for monogenetic causes of amyotrophic lateral sclerosis has already led to genetically stratified treatment trials that bring additional considerations including the nature of the control arm.(67,68) Regardless of how drugs are selected, the pace of growth in…”
Backgroundvan den Berg, L. H., Rothstein, J. D., Shaw, P. J., Babu, S., Benatar, M., Bucelli, R. C., Genge, A. L., Glass, J. D., Hardiman, O. M., Libri, V., et al. (2024) · The Lancet Neurology · doi:10.1016/s1474-4422(24)00216-3 · Cited by 89
Self-citationAbati, E., Manini, A., Comi, G. P., & Corti, S. P. (2022) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-022-04408-w · Cited by 85
“Notably, tofersen, an antisense oligonucleotide, recently proved effective in a clinical trial on ALS patients carrying a mutation in the SOD1 gene [6].”
BackgroundJiang, J., Wang, Y., & Deng, M. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.1054006 · Cited by 88
“Most adverse events were mild to moderate, including headache, procedural pain, and postlumbar syndrome related to lumbar puncture (Miller et al., 2020).”
BackgroundThompson, A. G., Gray, E., Verber, N. S., Bobeva, Y., Lombardi, V., Shepheard, S. R., Yildiz, Ö., Feneberg, E., Farrimond, L. E., Dharmadasa, T., et al. (2022) · Brain Communications · doi:10.1093/braincomms/fcac029 · Cited by 84
“Consistent reduction in neurofilament levels has also recently been shown in trials of antisense oligonucleotide therapy in patients harbouring ALS-causing SOD1 mutations, providing an early suggestion that similar changeswill occurwith effective ALS treatment.(10) Our modelling suggested that using plasma NFL in plac…”
Self-citationRandomized, double-blind, placebo-controlled trial of rapamycin in amyotrophic lateral sclerosis
Mandrioli, J., D’Amico, R., Zucchi, E., Biasi, S. D., Banchelli, F., Martinelli, I., Simonini, C., Tartaro, D. L., Vicini, R., Fini, N., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-40734-8 · Cited by 88
“…fast disease progression to be associated with neuro fi lament decrease over time 29 , other observed an absence of correlation between a drug clinical effect and repeated neuro fi lament measurements 30,31 , others correlated a rise of serum NfL over time to a fast-progressing disease course 32 .”
Gene Therapy in Amyotrophic Lateral Sclerosis
Fang, T., Je, G., Pacut, P., Keyhanian, K., Gao, J., & Ghasemi, M. (2022) · Cells · doi:10.3390/cells11132066 · Cited by 88
“gov identifier: NCT02623699) and found a dose dependent efficacy with highest dose 100 mg showing the largest of effects at reducing CSF SOD1 concentration, especially in fast progressors of disease [35] (Table 1).”
BackgroundResultBlood-based biomarkers of inflammation in amyotrophic lateral sclerosis
Staats, K. A., Borchelt, D., Tansey, M. G., & Wymer, J. P. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00515-1 · Cited by 77
“ALS; initially by targeting of the SOD1 gene for ALS patients harboring an ALS-causing mutation in this gene in clinical trials [88], and with the additional development of”
BackgroundTDP-43 pathology: From noxious assembly to therapeutic removal
Keating, S. S., Gil, R. S., Swanson, M. E. V., Scotter, E. L., & Walker, A. K. (2022) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2022.102229 · Cited by 81
A perspective on therapies for amyotrophic lateral sclerosis: can disease progression be curbed?
Xu, X., Shen, D., Gao, Y., Zhou, Q., Ni, Y., Meng, H., Shi, H., Le, W., Chen, S., & Chen, S. (2021) · Translational Neurodegeneration · doi:10.1186/s40035-021-00250-5 · Cited by 81
“group, the ALSFRS-R score of the 100 mg tofersen group seemed to decrease slower than the placebo group [33].”
BackgroundMethodInfluentialJablonka, S., Hennlein, L., & Sendtner, M. (2022) · Neurological Research and Practice · doi:10.1186/s42466-021-00162-9 · Cited by 79
Li, Y., Liu, Y., Yu, X., Xu, Y., Pan, X., Sun, Y. E., Wang, Y., Song, Y.-H., & Shen, Z. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-02013-w · Cited by 72
Monine, M. I., Norris, D. A., Wang, Y., & Nestorov, I. A. (2021) · Journal of Pharmacokinetics and Pharmacodynamics · doi:10.1007/s10928-021-09761-0 · Cited by 70
Self-citationCurrent State and Future Directions in the Diagnosis of Amyotrophic Lateral Sclerosis
Vidovic, M., Müschen, L. H., Brakemeier, S., Machetanz, G., Naumann, M., & Castro‐Gomez, S. (2023) · Cells · doi:10.3390/cells12050736 · Cited by 73
“For patients with SOD1 mutations, tofersen, an antisense oligonucleotide reducing SOD1 protein synthesis, was shown to reduce neurofilament light chain levels in plasma and is already available in many countries in an early access program [84,85]; 3.”
BackgroundTherapeutically viable generation of neurons with antisense oligonucleotide suppression of PTB
Maimon, R., Chillon-Marinas, C., Snethlage, C. E., Singhal, S. M., McAlonis-Downes, M., Ling, K., Rigo, F., Bennett, C. F., Da Cruz, S., Hnasko, T. S., et al. (2021) · Nature Neuroscience · doi:10.1038/s41593-021-00864-y · Cited by 62
Self-citationEfficacy and long-term safety of CRISPR/Cas9 genome editing in the SOD1-linked mouse models of ALS
Deng, H., Zhai, H., Shi, Y., Liu, G., Lowry, J., Liu, B., Ryan, É. B., Yan, J., Yang, Y., Zhang, N., et al. (2021) · Communications Biology · doi:10.1038/s42003-021-01942-4 · Cited by 66
Huang, M., Liu, Y. U., Yao, X., Qin, D., & Su, H. (2024) · Translational Neurodegeneration · doi:10.1186/s40035-024-00416-x · Cited by 64
“ISIS 333611 which targets c.19–38 of wild-type SOD1 , now renamed Tofersen (BIIB067), has entered clinical trials [160] and shown promising results [161–165].”
BackgroundProtein aggregation and its affecting mechanisms in neurodegenerative diseases
Wu, J., Wu, J., Chen, T., Cai, J., & Ren, R. (2024) · Neurochemistry International · doi:10.1016/j.neuint.2024.105880 · Cited by 62
“Two patients with a pure SOD1 c.335dupG variant showed similar symptoms, including quadratic spatiality, progressive loss of locomotion, and hyperreflexia, with symptoms starting in early childhood (Mueller et al., 2020; Miller et al., 2020).”
Inhibition of HERV-K (HML-2) in amyotrophic lateral sclerosis patients on antiretroviral therapy
Montojo, M. G., Fathi, S., Norato, G., Smith, B., Rowe, D. B., Kiernan, M. C., Vucic, S., Mathers, S., van Eijk, R. P. A., Santamaria, U. A., et al. (2021) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2021.117358 · Cited by 58
The SOD1-mediated ALS phenotype shows a decoupling between age of symptom onset and disease duration
Opie-Martin, S., Iacoangeli, A., Topp, S. D., Abel, O., Mayl, K., Mehta, P. R., Shatunov, A., Fogh, I., Bowles, H., Limbachiya, N., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-34620-y · Cited by 58
“15 It is not clear what impact therapy will have on people carrying variants associated with a longer disease duration, although if effective, the therapy should halt progression altogether.”
Self-citationBlood biomarkers in ALS : challenges, applications and novel frontiers
Sturmey, E., & Malaspina, A. (2022) · Acta Neurologica Scandinavica · doi:10.1111/ane.13698 · Cited by 56
The sense of antisense therapies in ALS
Daele, S. H. V., Masrori, P., Damme, P. V., & Bosch, L. V. D. (2024) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2023.12.003 · Cited by 61
The Role of VCP Mutations in the Spectrum of Amyotrophic Lateral Sclerosis—Frontotemporal Dementia
Scarian, E., Fiamingo, G., Diamanti, L., Palmieri, I., Gagliardi, S., & Pansarasa, O. (2022) · Frontiers in Neurology · doi:10.3389/fneur.2022.841394 · Cited by 56
Cullen, N. C., Novák, P., Tosun, D., Kováčech, B., Hanes, J., Kontseková, E., Fresser, M., Ropele, S., Feldman, H., Schmidt, R., et al. (2023) · EBioMedicine · doi:10.1016/j.ebiom.2023.104923 · Cited by 55
“11,12 The CDR-SB and ADCS-MCI-ADL are widely employed as clinical Sex (% male/female) a 41.4 outcome measures in AD trials; and would be expected to be less sensitive to treatment effects than biomarkers.”
MethodInfluentialAbu‐Rumeileh, S., Baiardi, S., Ladogana, A., Zenesini, C., Bartoletti‐Stella, A., Poleggi, A., Mammana, A., Polischi, B., Pocchiari, M., Capellari, S., et al. (2020) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp-2020-323826 · Cited by 55
“29 The discussion of the present results should also consider the current clinical scenario.”
Inflammasome Contribution to the Activation of Th1, Th2, and Th17 Immune Responses
Martynova, E. V., Rizvanov, A. A., Urbanowicz, R. A., & Khaiboullina, S. F. (2022) · Frontiers in Microbiology · doi:10.3389/fmicb.2022.851835 · Cited by 54
Pan, Y., & Nicolazzo, J. A. (2022) · British Journal of Pharmacology · doi:10.1111/bph.15802 · Cited by 49
Metabolic alterations precede neurofilament changes in presymptomatic ALS gene carriers
Dorst, J., Weydt, P., Brenner, D., Witzel, S., Kandler, K., Huss, A. M., Herrmann, C. H., Wiesenfarth, M., Knehr, A., Günther, K., et al. (2023) · EBioMedicine · doi:10.1016/j.ebiom.2023.104521 · Cited by 53
Self-citationvan Roon‐Mom, W., Ferguson, C. M., & Aartsma-Rus, A. M. (2023) · Nucleic Acid Therapeutics · doi:10.1089/nat.2023.0027 · Cited by 51
The presymptomatic phase of amyotrophic lateral sclerosis: are we merely scratching the surface?
Chipika, R. H., Siah, W. F., McKenna, M. C., Shing, S. L. H., Hardiman, O. M., & Bede, P. (2020) · Journal of Neurology · doi:10.1007/s00415-020-10289-5 · Cited by 54
The 2022 Lady Estelle Wolfson lectureship on neurofilaments
Petzold, A. (2022) · Journal of Neurochemistry · doi:10.1111/jnc.15682 · Cited by 52
“Nf stoichiometry changes in ALS (Khalil et al., 2018).”
BackgroundMethodInfluentialKetabforoush, A. H. M. E., Chegini, R., Barati, S., Tahmasebi, F., Moghisseh, B., Joghataei, M. T., Faghihi, F., & Azedi, F. (2023) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2023.114378 · Cited by 54
Trist, B. G., Fifita, J. A., Hogan, A. L., Grima, N., Smith, B. N., Troakes, C., Vance, C. A., Shaw, C. E., Al‐Sarraj, S., Blair, I. P., et al. (2022) · Acta Neuropathologica Communications · doi:10.1186/s40478-022-01421-9 · Cited by 53
“Current therapies targeting disordered SOD1 and pathological TDP-43 in ALS patients primarily aim to reduce expression levels [31], stabilize protein structure [3, 38, 49], correct protein mislocalization [6] or enhance clearance mechanisms [9].”
BackgroundImamura, K., Izumi, Y., Nagai, M., Nishiyama, K., Watanabe, Y., Hanajima, R., Egawa, N., Ayaki, T., Oki, R., Fujita, K., et al. (2022) · EClinicalMedicine · doi:10.1016/j.eclinm.2022.101707 · Cited by 50
De novo mutations in SOD1 are a cause of ALS
Müller, K., Oh, K., Nordin, A., Panthi, S., Kim, S. H., Nordin, F., Freischmidt, A., Ludolph, A. C., Ki, C., Forsberg, K., et al. (2021) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp-2021-327520 · Cited by 49
“The findings of increasing number of sALS cases to have a genetic underpinning coupled with the promising results from new bespoken gene therapies 40 make us revise our previous opinion.”
Self-citationCerebrospinal fluid biomarkers of disease activity and progression in amyotrophic lateral sclerosis
Dreger, M., Steinbach, R., Otto, M., Turner, M. R., & Großkreutz, J. (2022) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp-2021-327503 · Cited by 49
Saini, A., & Chawla, P. A. (2023) · European Journal of Neurology · doi:10.1111/ene.16140 · Cited by 49
The Biogenesis of miRNAs and Their Role in the Development of Amyotrophic Lateral Sclerosis
Liu, J., Zhou, F., Guan, Y., Meng, F., Zhao, Z., Su, Q., Bao, W., Wang, X., Zhao, J., Huo, Z., et al. (2022) · Cells · doi:10.3390/cells11030572 · Cited by 55
Genetic testing in motor neurone disease
Dharmadasa, T., Scaber, J., Edmond, E., Marsden, R., Thompson, A., Talbot, K., & Turner, M. R. (2022) · Practical Neurology · doi:10.1136/practneurol-2021-002989 · Cited by 48
Targeting RNA with synthetic oligonucleotides: Clinical success invites new challenges
Hofman, C. R., & Corey, D. R. (2023) · Cell chemical biology · doi:10.1016/j.chembiol.2023.09.005 · Cited by 56
The impact of age on genetic testing decisions in amyotrophic lateral sclerosis
Mehta, P. R., Iacoangeli, A., Opie-Martin, S., van Vugt, J. J. F. A., Khleifat, A. A., Bredin, A., Ossher, L., Andersen, P. M., Hardiman, O. M., Mehta, A. R., et al. (2022) · Brain · doi:10.1093/brain/awac279 · Cited by 48
“There is mounting evidence that for those with an identified genetic basis to their ALS, effective treatment may soon be possible.(4,5)”
Self-citationBarresi, V., Musmeci, C., Rinaldi, A., & Condorelli, D. F. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23168875 · Cited by 52
Helm, J., Schöls, L. J., & Hauser, S. (2022) · Pharmaceutics · doi:10.3390/pharmaceutics14081708 · Cited by 50
α-Synuclein: A Promising Biomarker for Parkinson’s Disease and Related Disorders
Hatano, T., Okuzumi, A., Matsumoto, G., Tsunemi, T., & Hattori, N. (2024) · Journal of Movement Disorders · doi:10.14802/jmd.24075 · Cited by 49
“Additionally, when evaluating the effectiveness of treatments for amyotrophic lateral sclerosis, such as SOD1 antisense oligonucleotides, 88 the combination of Amylyx and sodium phenylbutyrate, 89 and C9orf72 antisense oligonucleotides, 90 the development of surrogate markers that align with the…”
BackgroundPaving the Way Toward Meaningful Trials in Ataxias: An Ataxia Global Initiative Perspective
Klockgether, T., Ashizawa, T., Brais, B., Chuang, R., Dürr, A., Fogel, B. L., Greenfield, J., Hagen, S., Jardim, L. B., Jiang, H. F., et al. (2022) · Movement Disorders · doi:10.1002/mds.29032 · Cited by 45
“Such ASOs already underwent successful early-phase clinical trials in Huntington’s disease and superoxide dismutase 1 amyotrophic lateral sclerosis (SOD1 ALS).(5,6) However, subsequent phase 3 trials did not prove clinical efficacy, but a positive effect on fluid biomarkers in SOD1 ALS (https:// investors.”
BackgroundBiomarker discovery and development for frontotemporal dementia and amyotrophic lateral sclerosis
Katzeff, J. S., Bright, F., Phan, K., Kril, J. J., Ittner, L. M., Kassiou, M., Hodges, J. R., Piguet, O., Kiernan, M. C., Halliday, G. M., et al. (2022) · Brain · doi:10.1093/brain/awac077 · Cited by 48
“ever, a correlation between treatment and clinical outcomes could not be drawn due to the small study size.(63) Therefore, the use of SOD1 as a biomarker may lie primarily in determining the pharma-”
BackgroundConsiderations for Amyotrophic Lateral Sclerosis (ALS) Clinical Trial Design
Fournier, C. N. (2022) · Neurotherapeutics · doi:10.1007/s13311-022-01271-2 · Cited by 45
“Recent studies highlight these uncertainties; the phase 1–2 study of Tofersen in SOD1 ALS showed reduction of neurofilament light chains with treatment without a corresponding benefit on clinical outcome measures [99], while the AMX0035 study showed benefit on its primary clinical outcome measure without a significant…”
Result
Metadata
- Authors
- Miller, T., Cudkowicz, M., Shaw, P. J., Andersen, P. M., Atassi, N., Bucelli, R. C., Genge, A., Glass, J., Ladha, S., Ludolph, A. L., Maragakis, N. J., McDermott, C. J., Pestronk, A., Ravits, J., Salachas, F., Trudell, R., Van Damme, P., Zinman, L., Bennett, C. F., Lane, R., Sandrock, A., Runz, H., Graham, D., Houshyar, H., McCampbell, A., Nestorov, I., Chang, I., McNeill, M., Fanning, L., Fradette, S., & Ferguson, T. A.
- Affiliations
- 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...
- Harvard University (US)
- Montreal Neurological Institute and Hospital (CA)
- Barrow Neurological Institute (US)
- Biogen (United States) (US)
- ORCID
- Cudkowicz, Merit
- Shaw, Pamela J.
- Andersen, Peter M.
- Atassi, Nazem
- Bucelli, Robert C.
- Genge, Angela
- Glass, Jonathan
- Ladha, Shafeeq
- Maragakis, Nicholas J.
- McDermott, Christopher J.
- Pestronk, Alan
- Ravits, John
- Trudell, Randall
- Zinman, Lorne
- Bennett, C. Frank
- Lane, Roger
- Runz, Heiko
- Graham, Danielle
- McCampbell, Alexander
- Nestorov, Ivan
- Chang, Ih
- Fradette, Stephanie
- Ferguson, Toby A.
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2020-07-09
- Volume
- 383
- Issue
- 2
- Pages
- 109-119
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W3040840440
- Cited by
- 565
- References
- 27
- Citations by year
- 2026: 64 · 2025: 73 · 2024: 87 · 2023: 90 · 2022: 130 · 2021: 83 · 2020: 36
- FWCI
- 36.67
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Lirias (KU Leuven) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion, cc-by)
- Funders
- National Institute for Health and Care Research (NF-SI-0617-10077)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Genetics (clinical) › Neurogenetic and Muscular Disorders Research
- Keywords
- tofersen, antisense oligonucleotides, amyotrophic lateral sclerosis, SOD1, intrathecal administration, pleocytosis, dose escalation
- MeSH terms
- Superoxide Dismutase-1, Adult, Amyotrophic Lateral Sclerosis, Dose-Response Relationship, Drug, Double-Blind Method, Female, Headache, Humans, Injections, Spinal, Intermediate Filaments, Leukocytosis, Male, Middle Aged, Mutation, Oligonucleotides, Vital Capacity, Oligonucleotides, Antisense, Disease Progression
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
