{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T14:04:49Z","timestamp":1788185089647,"version":"build-2803163510"},"reference-count":159,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T00:00:00Z","timestamp":1763683200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T00:00:00Z","timestamp":1763683200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Orphanet J Rare Dis"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder affecting nerve cells in the brain and spinal cord. With a global incidence of 1.9 to 6 per 100,000 people, ALS is slightly more common in men and prevalent in individuals over 60. However, this review provides a concise update on the regulatory landscape and therapeutic advancements in managing ALS, focusing on the recent approval of Tofersen, the first gene therapy specifically targeting SOD1 mutation-related ALS.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>It highlights Tofersen unique role as an orphan drug approved by the US FDA, emphasizing its mechanism of action, gene silencing and its impact on reducing neurodegeneration. Additionally, the review synthesizes data from ongoing clinical trials, pharmacovigilance reports, and case studies to comprehensively understand Tofersen\u2019s safety, efficacy and market exclusivity. Beyond this, it explores the emerging potential of nanotherapeutic approaches to ALS treatment, identifying critical research gaps and future directions.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Integrating regulatory updates, clinical evidence, and innovative therapeutic strategies, the review uniquely contributes to the ALS literature by bridging current treatment realities with potential future therapies, aiming to inform researchers, clinicians, and policymakers on optimizing ALS management.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Graphical Abstract<\/jats:title>\n                  <\/jats:sec>","DOI":"10.1186\/s13023-025-04042-2","type":"journal-article","created":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T14:31:56Z","timestamp":1763735516000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Concurrent nanotherapeutics and regulatory updates for the management of amyotrophic lateral sclerosis: a focused review for orphan drug (Tofersen)"],"prefix":"10.1186","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0232-6317","authenticated-orcid":false,"given":"Abhiram","family":"Kumar","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-6395-6838","authenticated-orcid":false,"given":"Shivang","family":"Shukla","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-9037-325X","authenticated-orcid":false,"given":"Anjali","family":"Rai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4150-0058","authenticated-orcid":false,"given":"Priya","family":"Pathak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5198-2495","authenticated-orcid":false,"given":"Kumar Pranav","family":"Narayan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,21]]},"reference":[{"key":"4042_CR1","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1007\/978-3-030-32633-3_26","volume":"1195","author":"K Kadena","year":"2020","unstructured":"Kadena K, Vlamos P. Amyotrophic lateral sclerosis: current status in diagnostic biomarkers. Adv Exp Med Biol. 2020;1195:179\u201387.","journal-title":"Adv Exp Med Biol"},{"key":"4042_CR2","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1038\/s41573-022-00612-2","volume":"22","author":"RJ Mead","year":"2023","unstructured":"Mead RJ, Shan N, Reiser HJ, Marshall F, Shaw PJ. Amyotrophic lateral sclerosis: a neurodegenerative disorder poised for successful therapeutic translation. Nat Rev Drug Discov. 2023;22:185\u2013212.","journal-title":"Nat Rev Drug Discov"},{"key":"4042_CR3","doi-asserted-by":"publisher","first-page":"1099","DOI":"10.1056\/NEJMoa2204705","volume":"387","author":"TM Miller","year":"2022","unstructured":"Miller TM, Cudkowicz ME, Genge A, Shaw PJ, Sobue G, Bucelli RC, et al. Trial of antisense oligonucleotide Tofersen for SOD1 ALS. N Engl J Med. 2022;387:1099\u2013110.","journal-title":"N Engl J Med"},{"key":"4042_CR4","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1002\/acn3.52264","volume":"12","author":"SE Smith","year":"2025","unstructured":"Smith SE, McCoy-Gross K, Malcolm A, Oranski J, Markway JW, Miller TM, et al. Tofersen treatment leads to sustained stabilization of disease in SOD1 ALS in a real-world setting. Ann Clin Transl Neurol. 2025;12:311\u20139.","journal-title":"Ann Clin Transl Neurol"},{"key":"4042_CR5","doi-asserted-by":"crossref","unstructured":"Mehta P, Raymond J, Zhang Y, Punjani R, Han M, Larson T et al. Prevalence of amyotrophic lateral sclerosis in the united States, 2018. Amyotroph Lateral Scler Frontotemporal Degener. 2023. p. 1\u20137.","DOI":"10.1080\/21678421.2023.2245858"},{"key":"4042_CR6","unstructured":"CDC. National Amyotrophic Lateral Sclerosis (ALS) Registry and Biorepository. 2020 ATSDR Annual Report; 2024. https:\/\/www.atsdr.cdc.gov\/2020-annual-report\/php\/national-als-registry-and-biorepository.html. Accessed 15 Jul 2025."},{"key":"4042_CR7","doi-asserted-by":"publisher","first-page":"290","DOI":"10.1080\/21678421.2024.2447919","volume":"26","author":"P Mehta","year":"2025","unstructured":"Mehta P, Raymond J, Nair T, Han M, Berry J, Punjani R, et al. Amyotrophic lateral sclerosis estimated prevalence cases from 2022 to 2030, data from the National ALS registry. Amyotroph Lateral Scler Frontotemporal Degener. 2025;26:290\u20135.","journal-title":"Amyotroph Lateral Scler Frontotemporal Degener"},{"key":"4042_CR8","unstructured":"Why this neurodegenerative disease needs. rare tag. The Times of India; 2023. https:\/\/timesofindia.indiatimes.com\/city\/delhi\/why-this-neurodegenerative-disease-needs-rare-tag\/articleshow\/101176187.cms. Accessed 15 Jul 2025."},{"key":"4042_CR9","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.adj9332","volume":"15","author":"TF Gendron","year":"2023","unstructured":"Gendron TF, Petrucelli L. Immunological drivers of amyotrophic lateral sclerosis. Sci Transl Med. 2023;15:eadj9332.","journal-title":"Sci Transl Med"},{"key":"4042_CR10","doi-asserted-by":"publisher","first-page":"1523","DOI":"10.3390\/cells12111523","volume":"12","author":"L Tzeplaeff","year":"2023","unstructured":"Tzeplaeff L, Wilfling S, Requardt MV, Herdick M. Current state and future directions in the therapy of ALS. Cells. 2023;12:1523.","journal-title":"Cells"},{"key":"4042_CR11","doi-asserted-by":"publisher","first-page":"3500","DOI":"10.1093\/brain\/awac185","volume":"145","author":"M Benatar","year":"2022","unstructured":"Benatar M, Granit V, Andersen PM, Grignon A-L, McHutchison C, Cosentino S, et al. Mild motor impairment as prodromal state in amyotrophic lateral sclerosis: a new diagnostic entity. Brain. 2022;145:3500\u20138.","journal-title":"Brain"},{"key":"4042_CR12","doi-asserted-by":"publisher","first-page":"6508","DOI":"10.1007\/s00415-024-12657-x","volume":"271","author":"B Bjelica","year":"2024","unstructured":"Bjelica B, Petri S. Narrative review of diagnosis, management, and treatment of dysphagia and sialorrhea in amyotrophic lateral sclerosis. J Neurol. 2024;271:6508\u201313.","journal-title":"J Neurol"},{"key":"4042_CR13","doi-asserted-by":"publisher","first-page":"1918","DOI":"10.1111\/ene.14393","volume":"27","author":"P Masrori","year":"2020","unstructured":"Masrori P, Van Damme P. Amyotrophic lateral sclerosis: a clinical review. Eur J Neurol. 2020;27:1918\u201329.","journal-title":"Eur J Neurol"},{"key":"4042_CR14","doi-asserted-by":"publisher","first-page":"1087098","DOI":"10.3389\/fgene.2023.1087098","volume":"14","author":"K Kaivola","year":"2023","unstructured":"Kaivola K, Pirinen M, Laaksovirta H, Jansson L, Rautila O, Launes J, et al. C9orf72 hexanucleotide repeat allele tagging snps: associations with ALS risk and longevity. Front Genet. 2023;14:1087098.","journal-title":"Front Genet"},{"key":"4042_CR15","doi-asserted-by":"publisher","first-page":"3760","DOI":"10.1093\/brain\/awad120","volume":"146","author":"SH Van Daele","year":"2023","unstructured":"Van Daele SH, Moisse M, van Vugt JJFA, Zwamborn RAJ, van der Spek R, van Rheenen W, et al. Genetic variability in sporadic amyotrophic lateral sclerosis. Brain. 2023;146:3760\u20139.","journal-title":"Brain"},{"key":"4042_CR16","unstructured":"Orange Book. Approved drug products with therapeutic equivalence evaluations. https:\/\/www.accessdata.fda.gov\/scripts\/cder\/ob\/results_product.cfm?Appl_Type=N&Appl_No=215887#42985.6. Accessed 15 July 2025."},{"key":"4042_CR17","unstructured":"Orange Book. Approved drug products with therapeutic equivalence evaluations. https:\/\/www.accessdata.fda.gov\/scripts\/cder\/ob\/index.cfm#44884.6. Accessed 15 July 2025."},{"key":"4042_CR18","unstructured":"Orange Book. Approved drug products with therapeutic equivalence evaluations. https:\/\/www.accessdata.fda.gov\/scripts\/cder\/ob\/results_product.cfm?Appl_Type=A&Appl_No=216035#44884.6. Accessed 15 July 2025."},{"key":"4042_CR19","unstructured":"Qalsody. European Medicines Agency (EMA); 2024. https:\/\/www.ema.europa.eu\/en\/medicines\/human\/EPAR\/qalsody. Accessed 15 July 2025."},{"key":"4042_CR20","doi-asserted-by":"publisher","first-page":"162","DOI":"10.1056\/NEJMra1603471","volume":"377","author":"RH Brown","year":"2017","unstructured":"Brown RH, Al-Chalabi A. Amyotrophic lateral sclerosis. N Engl J Med. 2017;377:162\u201372.","journal-title":"N Engl J Med"},{"key":"4042_CR21","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1038\/nature20413","volume":"539","author":"JP Taylor","year":"2016","unstructured":"Taylor JP, Brown RH, Cleveland DW. Decoding ALS: from genes to mechanism. Nature. 2016;539:197\u2013206.","journal-title":"Nature"},{"key":"4042_CR22","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2017.71","volume":"3","author":"O Hardiman","year":"2017","unstructured":"Hardiman O, Al-Chalabi A, Chio A, Corr EM, Logroscino G, Robberecht W, et al. Amyotrophic lateral sclerosis. Nat Rev Dis Primers. 2017;3:17071.","journal-title":"Nat Rev Dis Primers"},{"key":"4042_CR23","doi-asserted-by":"publisher","first-page":"1328","DOI":"10.2174\/0113816128329141241205063352","volume":"31","author":"A Rai","year":"2025","unstructured":"Rai A, Shukla S, Gupta RK, Mishra A. ALS: a silent slayer of motor neurons. Traditional Chinese herbal medicine as an effective therapy. Curr Pharm Des. 2025;31:1328\u201346.","journal-title":"Curr Pharm Des"},{"key":"4042_CR24","unstructured":"PubChem. Riluzole. https:\/\/pubchem.ncbi.nlm.nih.gov\/compound\/5070. Accessed 10 July 2025."},{"key":"4042_CR25","unstructured":"Search Orphan Drug Designations and Approvals. https:\/\/www.accessdata.fda.gov\/scripts\/opdlisting\/oopd\/detailedIndex.cfm?cfgridkey=072792. Accessed 24 July 2024."},{"key":"4042_CR26","unstructured":"Radicava. (edaravone) FDA Approval History. Drugs.com. https:\/\/www.drugs.com\/history\/radicava.html. Accessed 28 July 2025."},{"key":"4042_CR27","unstructured":"PubChem. Mci-186. https:\/\/pubchem.ncbi.nlm.nih.gov\/compound\/402. Accessed 27 July 2025."},{"key":"4042_CR28","unstructured":"PubChem. Sodium phenylbutyrate\/tauroursodeoxycholic acid. https:\/\/pubchem.ncbi.nlm.nih.gov\/compound\/12931649. Accessed 19 July 2025."},{"key":"4042_CR29","unstructured":"Relyvrio ALZFORUM. https:\/\/www.alzforum.org\/therapeutics\/relyvrio. Accessed 19 July 2025."},{"key":"4042_CR30","unstructured":"Amylyx Pharmaceuticals Announces FDA Approval of RELYVRIO\u2122 for the Treatment of ALS, Amylyx. https:\/\/www.amylyx.com\/news\/amylyx-pharmaceuticals-announces-fda-approval-of-relyvriotm-for-the-treatment-of-als. Accessed 19 July 2025."},{"key":"4042_CR31","unstructured":"PubChem. Tofersen. https:\/\/pubchem.ncbi.nlm.nih.gov\/substance\/507517373. Accessed 19 July 2025."},{"key":"4042_CR32","doi-asserted-by":"publisher","unstructured":"Tofersen. First approval: drugs. https:\/\/doi.org\/10.1007\/s40265-023-01904-6. Accessed 19 July 2025.","DOI":"10.1007\/s40265-023-01904-6"},{"key":"4042_CR33","unstructured":"Pharma AL-S, Multicenter A, Label O. Single-Ascending Dose Study to Evaluate Safety, Tolerability, and Pharmacokinetics of AP-101 in Familial and Sporadic Amyotrophic Lateral Sclerosis (ALS). clinicaltrials.gov; 2020 Oct. Report No.: NCT03981536. https:\/\/clinicaltrials.gov\/study\/NCT03981536"},{"key":"4042_CR34","unstructured":"Ionis Pharmaceuticals. Inc. Phase 1\u20133 Study to Evaluate Efficacy, Safety, Pharmacokinetics and Pharmacodynamics of Intrathecally Administered ION363 in Amyotrophic Lateral Sclerosis Patients with Fused in Sarcoma Mutations (FUS-ALS). clinicaltrials.gov; 2024 Nov. Report No.: NCT04768972. https:\/\/clinicaltrials.gov\/study\/NCT04768972"},{"key":"4042_CR35","doi-asserted-by":"publisher","first-page":"2075","DOI":"10.1016\/S0140-6736(25)00513-6","volume":"405","author":"NA Shneider","year":"2025","unstructured":"Shneider NA, Harms MB, Korobeynikov VA, Rifai OM, Hoover BN, Harrington EA, et al. Antisense oligonucleotide jacifusen for FUS-ALS: an investigator-initiated, multicentre, open-label case series. The Lancet. 2025;405:2075\u201386.","journal-title":"The Lancet."},{"key":"4042_CR36","doi-asserted-by":"publisher","first-page":"515","DOI":"10.1002\/mus.27818","volume":"67","author":"T Meyer","year":"2023","unstructured":"Meyer T, Schumann P, Weydt P, Petri S, Koc Y, Spittel S, et al. Neurofilament light-chain response during therapy with antisense oligonucleotide Tofersen in SOD1-related ALS: treatment experience in clinical practice. Muscle Nerve. 2023;67:515\u201321.","journal-title":"Muscle Nerve"},{"key":"4042_CR37","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1056\/NEJMoa2003715","volume":"383","author":"T Miller","year":"2020","unstructured":"Miller T, Cudkowicz M, Shaw PJ, Andersen PM, Atassi N, Bucelli RC, et al. Phase 1\u20132 trial of antisense oligonucleotide Tofersen for SOD1 ALS. N Engl J Med. 2020;383:109\u201319.","journal-title":"N Engl J Med"},{"key":"4042_CR38","unstructured":"Tofersen (Qalsody). Use of a surrogate endpoint to demonstrate substantial evidence of effectiveness for an accelerated approval."},{"key":"4042_CR39","doi-asserted-by":"publisher","DOI":"10.1111\/ene.16140","volume":"31","author":"A Saini","year":"2024","unstructured":"Saini A, Chawla PA. Breaking barriers with tofersen: enhancing therapeutic opportunities in amyotrophic lateral sclerosis. Eur J Neurol. 2024;31:e16140.","journal-title":"Eur J Neurol"},{"key":"4042_CR40","doi-asserted-by":"publisher","first-page":"3315","DOI":"10.3390\/cimb45040217","volume":"45","author":"L L\u00f3pez-Pingarr\u00f3n","year":"2023","unstructured":"L\u00f3pez-Pingarr\u00f3n L, Almeida H, Soria-Aznar M, Reyes-Gonzales MC, Terr\u00f3n MP, Garc\u00eda JJ. Role of oxidative stress on the etiology and pathophysiology of amyotrophic lateral sclerosis (ALS) and its relationship with the enteric nervous system. Curr Issues Mol Biol. 2023;45:3315\u201332.","journal-title":"Curr Issues Mol Biol"},{"key":"4042_CR41","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22126352","volume":"22","author":"E Obrador","year":"2021","unstructured":"Obrador E, Salvador-Palmer R, L\u00f3pez-Blanch R, Jihad-Jebbar A, Vall\u00e9s SL, Estrela JM. The link between oxidative stress, redox status, bioenergetics and mitochondria in the pathophysiology of ALS. Int J Mol Sci. 2021;22:6352.","journal-title":"Int J Mol Sci"},{"key":"4042_CR42","doi-asserted-by":"publisher","DOI":"10.3390\/antiox11040614","volume":"11","author":"C Peggion","year":"2022","unstructured":"Peggion C, Scalcon V, Massimino ML, Nies K, Lopreiato R, Rigobello MP, et al. SOD1 in ALS: taking stock in pathogenic mechanisms and the role of glial and muscle cells. Antioxidants. 2022;11:614.","journal-title":"Antioxidants"},{"key":"4042_CR43","doi-asserted-by":"publisher","first-page":"1170996","DOI":"10.3389\/fnins.2023.1170996","volume":"17","author":"H Wang","year":"2023","unstructured":"Wang H, Guan L, Deng M. Recent progress of the genetics of amyotrophic lateral sclerosis and challenges of gene therapy. Front Neurosci. 2023;17:1170996.","journal-title":"Front Neurosci"},{"key":"4042_CR44","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-021-03891-8","volume":"12","author":"M Berdy\u0144ski","year":"2022","unstructured":"Berdy\u0144ski M, Miszta P, Safranow K, Andersen PM, Morita M, Filipek S, et al. SOD1 mutations associated with amyotrophic lateral sclerosis analysis of variant severity. Sci Rep. 2022;12:103.","journal-title":"Sci Rep"},{"key":"4042_CR45","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1016\/B978-0-12-802257-3.00004-3","volume-title":"Molecular and cellular therapies for motor neuron diseases","author":"M Collins","year":"2017","unstructured":"Collins M, Bowser R. Chapter 4\u2014Molecular mechanisms of amyotrophic lateral sclerosis. In: Boulis N, O\u2019Connor D, Donsante A, editors. Molecular and cellular therapies for motor neuron diseases. Academic Press; 2017. p. 61\u201399."},{"key":"4042_CR46","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1016\/j.neuron.2011.09.011","volume":"72","author":"M DeJesus-Hernandez","year":"2011","unstructured":"DeJesus-Hernandez M, Mackenzie IR, Boeve BF, Boxer AL, Baker M, Rutherford NJ, et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron. 2011;72:245\u201356.","journal-title":"Neuron"},{"key":"4042_CR47","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1016\/j.neuron.2011.09.010","volume":"72","author":"AE Renton","year":"2011","unstructured":"Renton AE, Majounie E, Waite A, Sim\u00f3n-S\u00e1nchez J, Rollinson S, Gibbs JR, et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron. 2011;72:257\u201368.","journal-title":"Neuron"},{"key":"4042_CR48","doi-asserted-by":"publisher","first-page":"496","DOI":"10.1016\/j.stemcr.2016.02.011","volume":"6","author":"N Ichiyanagi","year":"2016","unstructured":"Ichiyanagi N, Fujimori K, Yano M, Ishihara-Fujisaki C, Sone T, Akiyama T, et al. Establishment of in vitro FUS-associated familial amyotrophic lateral sclerosis model using human induced pluripotent stem cells. Stem Cell Rep. 2016;6:496\u2013510.","journal-title":"Stem Cell Rep"},{"key":"4042_CR49","doi-asserted-by":"publisher","first-page":"1066","DOI":"10.1016\/j.cell.2015.07.047","volume":"162","author":"A Patel","year":"2015","unstructured":"Patel A, Lee HO, Jawerth L, Maharana S, Jahnel M, Hein MY, et al. A liquid-to-solid phase transition of the ALS protein FUS accelerated by disease mutation. Cell. 2015;162:1066\u201377.","journal-title":"Cell"},{"key":"4042_CR50","doi-asserted-by":"publisher","first-page":"1604","DOI":"10.1093\/hmg\/ddm110","volume":"16","author":"D Sau","year":"2007","unstructured":"Sau D, De Biasi S, Vitellaro-Zuccarello L, Riso P, Guarnieri S, Porrini M, et al. Mutation of SOD1 in ALS: a gain of a loss of function. Hum Mol Genet. 2007;16:1604\u201318.","journal-title":"Hum Mol Genet"},{"key":"4042_CR51","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1016\/j.gene.2015.11.049","volume":"577","author":"SJ Kaur","year":"2016","unstructured":"Kaur SJ, McKeown SR, Rashid S. Mutant SOD1 mediated pathogenesis of amyotrophic lateral sclerosis. Gene. 2016;577:109\u201318.","journal-title":"Gene"},{"key":"4042_CR52","doi-asserted-by":"publisher","first-page":"130","DOI":"10.1126\/science.1134108","volume":"314","author":"M Neumann","year":"2006","unstructured":"Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT, et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science. 2006;314:130\u20133.","journal-title":"Science"},{"key":"4042_CR53","doi-asserted-by":"publisher","first-page":"602","DOI":"10.1016\/j.bbrc.2006.10.093","volume":"351","author":"T Arai","year":"2006","unstructured":"Arai T, Hasegawa M, Akiyama H, Ikeda K, Nonaka T, Mori H, et al. TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem Biophys Res Commun. 2006;351:602\u201311.","journal-title":"Biochem Biophys Res Commun"},{"key":"4042_CR54","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1111\/neup.12153","volume":"35","author":"H Honda","year":"2015","unstructured":"Honda H, Hamasaki H, Wakamiya T, Koyama S, Suzuki SO, Fujii N, et al. Loss of hnRNPA1 in ALS spinal cord motor neurons with TDP-43-positive inclusions. Neuropathology. 2015;35:37\u201343.","journal-title":"Neuropathology."},{"key":"4042_CR55","doi-asserted-by":"publisher","first-page":"1043","DOI":"10.1038\/ng.3622","volume":"48","author":"W van Rheenen","year":"2016","unstructured":"van Rheenen W, Shatunov A, Dekker AM, McLaughlin RL, Diekstra FP, Pulit SL, et al. Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis. Nat Genet. 2016;48:1043\u20138.","journal-title":"Nat Genet"},{"key":"4042_CR56","doi-asserted-by":"publisher","first-page":"465","DOI":"10.1080\/07391102.2018.1429313","volume":"37","author":"S Iyer","year":"2019","unstructured":"Iyer S, Acharya KR, Subramanian V. Prediction of structural consequences for disease causing variants in C21orf2 protein using computational approaches. J Biomol Struct Dyn. 2019;37:465\u201380.","journal-title":"J Biomol Struct Dyn"},{"key":"4042_CR57","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awv367","volume":"139","author":"B Jiao","year":"2016","unstructured":"Jiao B, Xiao T, Hou L, Gu X, Zhou Y, Zhou L, et al. High prevalence of CHCHD10 mutation in patients with frontotemporal dementia from China. Brain. 2016;139:e21. https:\/\/doi.org\/10.1093\/brain\/awv367.","journal-title":"Brain"},{"key":"4042_CR58","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awv175","volume":"138","author":"O Dols-Icardo","year":"2015","unstructured":"Dols-Icardo O, Nebot I, Gorostidi A, Ortega-Cubero S, Hern\u00e1ndez I, Rojas-Garc\u00eda R, et al. Analysis of the CHCHD10 gene in patients with frontotemporal dementia and amyotrophic lateral sclerosis from Spain. Brain. 2015;138:e400.","journal-title":"Brain"},{"key":"4042_CR59","doi-asserted-by":"publisher","first-page":"2329","DOI":"10.1093\/brain\/awu138","volume":"137","author":"S Bannwarth","year":"2014","unstructured":"Bannwarth S, Ait-El-Mkadem S, Chaussenot A, Genin EC, Lacas-Gervais S, Fragaki K, et al. Mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement. Brain. 2014;137:2329\u201345.","journal-title":"Brain"},{"key":"4042_CR60","doi-asserted-by":"publisher","first-page":"1037","DOI":"10.1038\/ng.3626","volume":"48","author":"KP Kenna","year":"2016","unstructured":"Kenna KP, Van Doormaal PT, Dekker AM, Ticozzi N, Kenna BJ, Diekstra FP, et al. NEK1 variants confer susceptibility to amyotrophic lateral sclerosis. Nat Genet. 2016;48:1037\u201342.","journal-title":"Nat Genet"},{"key":"4042_CR61","doi-asserted-by":"publisher","first-page":"76","DOI":"10.15698\/cst2020.04.217","volume":"4","author":"G Picchiarelli","year":"2020","unstructured":"Picchiarelli G, Dupuis L. Role of RNA Binding Proteins with prison-like domains in muscle and neuromuscular diseases. Cell Stress. 2020;4:76.","journal-title":"Cell Stress"},{"key":"4042_CR62","doi-asserted-by":"publisher","first-page":"5304","DOI":"10.1038\/s41467-020-18949-w","volume":"11","author":"CS Kao","year":"2020","unstructured":"Kao CS, van Bruggen R, Kim JR, Chen XX, Chan C, Lee J. Selective neuronal degeneration in MATR3 S85C knock-in mouse model of early-stage ALS. Nat Commun. 2020;11:5304.","journal-title":"Nat Commun"},{"key":"4042_CR63","doi-asserted-by":"publisher","first-page":"20881","DOI":"10.1073\/pnas.1109434108","volume":"108","author":"J Couthouis","year":"2011","unstructured":"Couthouis J, Hart MP, Shorter J, De Jesus-Hernandez M, Erion R, Oristano R. A yeast functional screen predicts new candidate ALS disease genes. Proc Natl Acad Sci USA. 2011;108:20881\u201390.","journal-title":"Proc Natl Acad Sci USA"},{"key":"4042_CR64","doi-asserted-by":"publisher","first-page":"12143","DOI":"10.1038\/ncomms12143","volume":"7","author":"K Kapeli","year":"2016","unstructured":"Kapeli K, Pratt GA, Vu AQ, Hutt KR, Martinez FJ, Sundararaman B. Distinct and shared functions of ALS-associated proteins TDP-43, FUS and TAF15 revealed by multisystem analyses. Nat Commun. 2016;7:12143.","journal-title":"Nat Commun"},{"key":"4042_CR65","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1002\/ajmg.b.31158","volume":"156B","author":"N Ticozzi","year":"2011","unstructured":"Ticozzi N, Vance C, Leclerc AL, Keagle P, Glass JD, McKenna-Yasek D, et al. Mutational analysis reveals the FUS homolog TAF15 as a candidate gene for familial amyotrophic lateral sclerosis. Am J Med Genet Part B Neuropsychiatr Genet. 2011;156B:285\u201390.","journal-title":"Am J Med Genet Part B Neuropsychiatr Genet."},{"key":"4042_CR66","doi-asserted-by":"publisher","first-page":"1193","DOI":"10.1007\/s00439-017-1830-7","volume":"136","author":"K Kapeli","year":"2017","unstructured":"Kapeli K, Martinez FJ, Yeo GW. Genetic mutations in RNA-binding proteins and their roles in ALS. Human Genet. 2017;136:1193\u2013214.","journal-title":"Human Genet"},{"key":"4042_CR67","doi-asserted-by":"publisher","first-page":"1069","DOI":"10.1038\/nature09320","volume":"466","author":"AC Elden","year":"2010","unstructured":"Elden AC, Kim HJ, Hart MP, Chen-Plotkin AS, Johnson BS, et al. Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS. Nature. 2010;466:1069\u201375.","journal-title":"Nature."},{"key":"4042_CR68","doi-asserted-by":"publisher","first-page":"767","DOI":"10.1002\/(SICI)1097-4547(20000315)59:6<767::AID-JNR9>3.0.CO;2-K","volume":"59","author":"K Jin","year":"2000","unstructured":"Jin K, Li W, Nagayama T, He X, Sinor AD, Chang J, et al. Expression of the RNA-binding protein TIAR is increased in neurons after ischemic cerebral injury. J Neurosci Res. 2000;59:767\u201374.","journal-title":"J Neurosci Res"},{"key":"4042_CR69","doi-asserted-by":"publisher","DOI":"10.3390\/ijms19082280","volume":"19","author":"S Ravanidis","year":"2018","unstructured":"Ravanidis S, Kattan F-G, Doxakis E. Unraveling the pathways to neuronal homeostasis and disease: mechanistic insights into the role of RNA-binding proteins and associated factors. Int J Mol Sci. 2018;19:2280.","journal-title":"Int J Mol Sci"},{"key":"4042_CR70","doi-asserted-by":"publisher","first-page":"1436","DOI":"10.1126\/science.aaa3650","volume":"347","author":"ET Cirulli","year":"2015","unstructured":"Cirulli ET, Lasseigne BN, Petrovski S, Sapp PC, Dion PA, Leblond CS, et al. Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways. Science. 2015;347:1436\u201341.","journal-title":"Science"},{"key":"4042_CR71","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1001\/jamaneurol.2016.3712","volume":"74","author":"A Freischmidt","year":"2017","unstructured":"Freischmidt A, M\u00fcller K, Ludolph AC, Weishaupt JH, Andersen PM. Association of mutations in TBK1 with sporadic and familial amyotrophic lateral sclerosis and frontotemporal dementia. JAMA Neurol. 2017;74:110\u20133.","journal-title":"JAMA Neurol"},{"key":"4042_CR72","doi-asserted-by":"publisher","first-page":"324","DOI":"10.1016\/j.neuron.2014.09.027","volume":"84","author":"BN Smith","year":"2014","unstructured":"Smith BN, Ticozzi N, Fallini C, Gkazi AS, Topp S, Kenna KP, et al. Exome-wide rare variant analysis identifies TUBA4A mutations associated with Familial ALS. Neuron. 2014;84:324\u201331.","journal-title":"Neuron"},{"key":"4042_CR73","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms11253","volume":"7","author":"KL Williams","year":"2016","unstructured":"Williams KL, Topp S, Yang S, Smith B, Fifita JA, Warraich ST, et al. Ccnf mutations in amyotrophic lateral sclerosis and frontotemporal dementia. Nat Commun. 2016;7:11253.","journal-title":"Nat Commun"},{"key":"4042_CR74","doi-asserted-by":"publisher","first-page":"1267","DOI":"10.1016\/j.neuron.2018.02.027","volume":"97","author":"A Nicolas","year":"2018","unstructured":"Nicolas A, Kenna KP, Renton AE, Ticozzi N, Faghri F, Chia R, et al. Genome-wide analyses identify KIF5A as a novel ALS gene. Neuron. 2018;97:1267\u201388.","journal-title":"Neuron"},{"key":"4042_CR75","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aax3993","volume":"12","author":"M Nahm","year":"2020","unstructured":"Nahm M, Lim SM, Kim Y-E, Park J, Noh M-Y, Lee S, et al. ANXA11 mutations in ALS cause dysregulation of calcium homeostasis and stress granule dynamics. Sci Transl Med. 2020;12:eaax3993.","journal-title":"Sci Transl Med"},{"key":"4042_CR76","doi-asserted-by":"publisher","first-page":"2298","DOI":"10.1016\/j.celrep.2019.02.006","volume":"26","author":"J Cooper-Knock","year":"2019","unstructured":"Cooper-Knock J, Moll T, Ramesh T, Castelli L, Beer A, Robins H, et al. Mutations in the glycosyltransferase domain of GLT8D1 are associated with Familial amyotrophic lateral sclerosis. Cell Rep. 2019;26:2298\u2013e23065.","journal-title":"Cell Rep"},{"key":"4042_CR77","doi-asserted-by":"publisher","first-page":"591","DOI":"10.1093\/brain\/awp325","volume":"133","author":"A Orlacchio","year":"2010","unstructured":"Orlacchio A, Babalini C, Borreca A, Patrono C, Massa R, Basaran S, et al. Spatacsin mutations cause autosomal recessive juvenile amyotrophic lateral sclerosis. Brain. 2010;133:591\u20138.","journal-title":"Brain"},{"key":"4042_CR78","doi-asserted-by":"publisher","DOI":"10.3390\/cells7110219","volume":"7","author":"C Ricci","year":"2018","unstructured":"Ricci C, Marzocchi C, Battistini S. Micrornas as biomarkers in amyotrophic lateral sclerosis. Cells. 2018;7:219.","journal-title":"Cells"},{"key":"4042_CR79","doi-asserted-by":"publisher","first-page":"731","DOI":"10.3389\/fnins.2017.00731","volume":"11","author":"R Waller","year":"2017","unstructured":"Waller R, Wyles M, Heath PR, Kazoka M, Wollff H, Shaw PJ, et al. Small RNA sequencing of sporadic amyotrophic lateral sclerosis cerebrospinal fluid reveals differentially expressed MiRNAs related to neural and glial activity. Front Neurosci. 2017;11:731.","journal-title":"Front Neurosci"},{"key":"4042_CR80","doi-asserted-by":"publisher","first-page":"4127","DOI":"10.1093\/hmg\/ddt261","volume":"22","author":"ED Koval","year":"2013","unstructured":"Koval ED, Shaner C, Zhang P, du Maine X, Fischer K, Tay J, et al. Method for widespread microrna-155 inhibition prolongs survival in ALS-model mice. Hum Mol Genet. 2013;22:4127\u201335.","journal-title":"Hum Mol Genet"},{"key":"4042_CR81","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1111\/jnc.14229","volume":"145","author":"F Zhou","year":"2018","unstructured":"Zhou F, Zhang C, Guan Y, Chen Y, Lu Q, Jie L, et al. Screening the expression characteristics of several miRNAs in G93A-SOD1 transgenic mouse: altered expression of miRNA-124 is associated with astrocyte differentiation by targeting Sox2 and Sox9. J Neurochem. 2018;145:51\u201367.","journal-title":"J Neurochem"},{"key":"4042_CR82","first-page":"4207","volume":"55","author":"C Cunha","year":"2018","unstructured":"Cunha C, Santos C, Gomes C, Fernandes A, Correia AM, Sebasti\u00e3o AM, et al. Downregulated glia interplay and increased miRNA-155 as promising markers to track ALS at an early stage. Mol Neurobiol. 2018;55:4207\u201324.","journal-title":"Mol Neurobiol"},{"key":"4042_CR83","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21051714","volume":"21","author":"M Ravnik-Glava\u010d","year":"2020","unstructured":"Ravnik-Glava\u010d M, Glava\u010d D. Circulating RNAs as potential biomarkers in amyotrophic lateral sclerosis. Int J Mol Sci. 2020;21:1714.","journal-title":"Int J Mol Sci"},{"key":"4042_CR84","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1186\/1756-6606-6-31","volume":"6","author":"Y Nishimoto","year":"2013","unstructured":"Nishimoto Y, Nakagawa S, Hirose T, Okano HJ, Takao M, Shibata S, et al. The long non-coding RNA nuclear-enriched abundant transcript 1_2 induces paraspeckle formation in the motor neuron during the early phase of amyotrophic lateral sclerosis. Mol Brain. 2013;6:31.","journal-title":"Mol Brain"},{"key":"4042_CR85","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-20679-5","volume":"8","author":"S Gagliardi","year":"2018","unstructured":"Gagliardi S, Zucca S, Pandini C, Diamanti L, Bordoni M, Sproviero D, et al. Long non-coding and coding RNAs characterization in peripheral blood mononuclear cells and spinal cord from amyotrophic lateral sclerosis patients. Sci Rep. 2018;8:2378.","journal-title":"Sci Rep"},{"key":"4042_CR86","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-19609-2","volume":"8","author":"F Zhang","year":"2018","unstructured":"Zhang F, Zhang Q, Ke Y, Hao J, Lu L, Lu N, et al. Serum uric acid levels in patients with amyotrophic lateral sclerosis: a meta-analysis. Sci Rep. 2018;8:1100.","journal-title":"Sci Rep"},{"key":"4042_CR87","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1136\/jnnp-2017-317138","volume":"89","author":"P Steinacker","year":"2018","unstructured":"Steinacker P, Verde F, Fang L, Feneberg E, Oeckl P, Roeber S, et al. Chitotriosidase (CHIT1) is increased in microglia and macrophages in spinal cord of amyotrophic lateral sclerosis and cerebrospinal fluid levels correlate with disease severity and progression. J Neurol Neurosurg Psychiatry. 2018;89:239\u201347.","journal-title":"J Neurol Neurosurg Psychiatry"},{"key":"4042_CR88","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1136\/jnnp-2018-318704","volume":"90","author":"F Verde","year":"2019","unstructured":"Verde F, Steinacker P, Weishaupt JH, Kassubek J, Oeckl P, Halbgebauer S, et al. Neurofilament light chain in serum for the diagnosis of amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry. 2019;90:157\u201364.","journal-title":"J Neurol Neurosurg Psychiatry"},{"key":"4042_CR89","unstructured":"An efficacy, safety, tolerability, pharmacokinetics and pharmacodynamics study of biib067 in adults with inherited amyotrophic lateral sclerosis (ALS) (VALOR (Part C))\u2014Mayo Clinic. https:\/\/www.mayo.edu\/research\/clinical-trials\/cls-20468264. Accessed 16 July 2025."},{"key":"4042_CR90","unstructured":"Trial. Long-Term Evaluation of BIIB067 (Tofersen). ALS Therapy Development Institute. https:\/\/www.als.net\/als-trial-navigator\/296\/. Accessed 15 July 2025."},{"key":"4042_CR91","doi-asserted-by":"publisher","first-page":"648","DOI":"10.1097\/WCO.0000000000000594","volume":"31","author":"CV Ly","year":"2018","unstructured":"Ly CV, Miller TM. Emerging antisense oligonucleotide and viral therapies for amyotrophic lateral sclerosis. Curr Opin Neurol. 2018;31:648\u201354.","journal-title":"Curr Opin Neurol"},{"key":"4042_CR92","first-page":"e45489","volume":"15","author":"P Hoxhaj","year":"2023","unstructured":"Hoxhaj P, Hastings N, Kachhadia MP, Gupta R, Sindhu U, Durve SA, et al. Exploring advancements in the treatment of amyotrophic lateral sclerosis: a comprehensive review of current modalities and future prospects. Cureus. 2023;15:e45489.","journal-title":"Cureus"},{"key":"4042_CR93","doi-asserted-by":"publisher","first-page":"1052341","DOI":"10.3389\/fneur.2022.1052341","volume":"13","author":"G Gianferrari","year":"2022","unstructured":"Gianferrari G, Martinelli I, Simonini C, Zucchi E, Fini N, Carra S, et al. Case report: p. Glu134del SOD1 mutation in two apparently unrelated ALS patients with mirrored phenotype. Front Neurol. 2022;13:1052341.","journal-title":"Front Neurol"},{"key":"4042_CR94","doi-asserted-by":"publisher","DOI":"10.1186\/s42466-023-00305-0","volume":"6","author":"M Vidovic","year":"2024","unstructured":"Vidovic M, Menschikowski M, Freigang M, Lapp HS, G\u00fcnther R. Macrophage inclusions in cerebrospinal fluid following treatment initiation with antisense oligonucleotide therapies in motor neuron diseases. Neurol Res Pract. 2024;6:11.","journal-title":"Neurol Res Pract"},{"key":"4042_CR95","unstructured":"Tofersen. https:\/\/go.drugbank.com\/drugs\/DB14782. Accessed 15 July 2025."},{"key":"4042_CR96","volume-title":"Tofersen.\u00a0StatPearls","author":"JL Cerillo","year":"2025","unstructured":"Cerillo JL, Parmar M. Tofersen.\u00a0StatPearls. Treasure Island: StatPearls Publishing; 2025."},{"key":"4042_CR97","unstructured":"Research C, for DE and. FDA approves treatment of amyotrophic lateral sclerosis associated with a mutation in the SOD1 gene. FDA; 2024. https:\/\/www.fda.gov\/drugs\/news-events-human-drugs\/fda-approves-treatment-amyotrophic-lateral-sclerosis-associated-mutation-sod1-gene. Accessed 15 July 2025."},{"key":"4042_CR98","unstructured":"Biogen A. Study to evaluate efficacy, safety, tolerability, pharmacokinetics, and pharmacodynamics of BIIB067 administered to adult subjects with amyotrophic lateral sclerosis and confirmed superoxide dismutase 1 mutation. clinicaltrials.gov; 2023. Report No.: NCT02623699. https:\/\/clinicaltrials.gov\/study\/NCT02623699"},{"key":"4042_CR99","unstructured":"Tofersen Monograph for Professionals. Drugs.com. https:\/\/www.drugs.com\/monograph\/tofersen.html. Accessed 15 July 2025."},{"key":"4042_CR100","doi-asserted-by":"publisher","first-page":"1006","DOI":"10.1002\/mus.28372","volume":"71","author":"A Lovett","year":"2025","unstructured":"Lovett A, Chary S, Babu S, Bruneteau G, Glass JD, Karlsborg M, et al. Serious neurologic adverse events in Tofersen clinical trials for amyotrophic lateral sclerosis. Muscle Nerve. 2025;71:1006\u201315.","journal-title":"Muscle Nerve"},{"key":"4042_CR101","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp-2022-abn2.6","volume":"93","author":"P Shaw","year":"2022","unstructured":"Shaw P, Miller T, Cudkowicz M, Genge A, Sobue G, Nestorov I, et al. Tofersen in adults with SOD1-ALS: phase 3 VALOR trial and open-label extension results. J Neurol Neurosurg Psychiatry. 2022;93:e2.","journal-title":"J Neurol Neurosurg Psychiatry."},{"key":"4042_CR102","doi-asserted-by":"publisher","unstructured":"Long-term treatment of SOD1 ALS. with Tofersen: a multicentre experience in 17 patients. J Neurol. https:\/\/link.springer.com\/article\/https:\/\/doi.org\/10.1007\/s00415-024-12437-7","DOI":"10.1007\/s00415-024-12437-7"},{"key":"4042_CR103","unstructured":"Tofersen decreases neurofilament levels. supporting the pathogenesis of the SOD1 p.D91A variant in amyotrophic lateral sclerosis patients: Communications Medicine.\u00a0https:\/\/www.nature.com\/articles\/s43856-024-00573"},{"key":"4042_CR104","unstructured":"Neurodegenerative. and neuroinflammatory changes in SOD1-ALS patients receiving Tofersen: Scientific Reports. https:\/\/www.nature.com\/articles\/s41598-025-94984-1. Accessed 23 July 2025."},{"key":"4042_CR105","doi-asserted-by":"crossref","unstructured":"Newman J, Corcia P, Genge A, Bucelli RC. SOD1-ALS from gene discovery to targeted therapeutics: a comprehensive review; 2025.\u00a0https:\/\/touchneurology.com\/brain-trauma\/journal-articles\/sod1-als-from-gene-discovery-to-targeted-therapeutics-a-comprehensive-review\/","DOI":"10.17925\/USN.2025.21.1.5"},{"key":"4042_CR106","doi-asserted-by":"publisher","first-page":"549","DOI":"10.1080\/14737175.2024.2355983","volume":"24","author":"M Oliveira Santos","year":"2024","unstructured":"Oliveira Santos M, de Carvalho M. Profiling tofersen as a treatment of superoxide dismutase 1 amyotrophic lateral sclerosis. Expert Rev Neurother. 2024;24:549\u201353. https:\/\/doi.org\/10.1080\/14737175.2024.2355983.","journal-title":"Expert Rev Neurother"},{"key":"4042_CR107","doi-asserted-by":"publisher","unstructured":"FDA accelerated approval of anticancer agents. J Clin Oncol. https:\/\/doi.org\/10.1200\/jco.2010.28.15_suppl.6065","DOI":"10.1200\/jco.2010.28.15_suppl.6065"},{"key":"4042_CR108","unstructured":"Capitalizing on Hope: questionable marketing approval and pricing of a new ALS drug\u2014Matthew B. Flynn, James F. Flynn, Ana M. Palacios; 2024. https:\/\/journals.sagepub.com\/doi\/10.1177\/27551938241247778"},{"key":"4042_CR109","unstructured":"Tofersen. (Qalsody) for ALS: the Medical Letter Inc. https:\/\/secure.medicalletter.org\/TML-article-1681a. Accessed 19 July 2025."},{"key":"4042_CR110","doi-asserted-by":"publisher","first-page":"S86","DOI":"10.1212\/WNL.47.4_Suppl_2.86S","volume":"47","author":"RG Miller","year":"1996","unstructured":"Miller RG, Bouchard JP, Duquette P, Eisen A, Gelinas D, Harati Y, et al. Clinical trials of riluzole in patients with ALS. Neurology. 1996;47:S86-92.","journal-title":"Neurology"},{"key":"4042_CR111","doi-asserted-by":"publisher","first-page":"p185","DOI":"10.1007\/978-3-031-89307-0_11","volume-title":"Translational neuroscience: fundamental approaches for neurological disorders","author":"SE Smith","year":"2025","unstructured":"Smith SE, Miller TM. Antisense oligonucleotides for amyotrophic lateral sclerosis. In: Tuszynski MH, editor. Translational neuroscience: fundamental approaches for neurological disorders. Cham: Springer Nature Switzerland; 2025. pp. p185\u2013200."},{"key":"4042_CR112","unstructured":"FDA approves treatment. of amyotrophic lateral sclerosis associated with a mutation in the SOD1 gene: FDA. https:\/\/www.fda.gov\/drugs\/news-events-human-drugs\/fda-approves-treatment-amyotrophic-lateral-sclerosis-associated-mutation-sod1-gene. Accessed 18 Jul 2025."},{"key":"4042_CR113","unstructured":"Biogen, Ionis Announce Discontinuation of BIIB078 in C9orf72-Associated ALS. Neurology live; 2022. https:\/\/www.neurologylive.com\/view\/biogen-ionis-discontine-biib078-c9orf72-associated-amyotrophic-lateral-sclerosis. Accessed 23 July 2025."},{"key":"4042_CR114","unstructured":"Biogen A. Phase 1 multiple-ascending-dose study to assess the safety, tolerability, and pharmacokinetics of BIIB078 administered intrathecally to adults with C9ORF72-associated amyotrophic lateral sclerosis. clinicaltrials.gov; 2022 Jan. Report No.: NCT03626012. https:\/\/clinicaltrials.gov\/study\/NCT03626012. Accessed 15 July 2025."},{"key":"4042_CR115","unstructured":"Wave Life Sciences Ltd, Multicenter A. Randomized, Double-blind, Placebo-controlled, Phase 1b\/2a Study of WVE-004 Administered Intrathecally to Patients with C9orf72-associated Amyotrophic Lateral Sclerosis (ALS) or Frontotemporal Dementia (FTD). clinicaltrials.gov; 2023 Oct. Report No.: NCT04931862. https:\/\/clinicaltrials.gov\/study\/NCT04931862. Accessed 26 July 2025."},{"key":"4042_CR116","unstructured":"Intellia Announces First Clinical Evidence from Ongoing Phase 1. Study that Nexiguran Ziclumeran (nex-z), an In Vivo CRISPR\/Cas9-Based Gene Editing Therapy, May Favorably Impact Disease Progression in Transthyretin (ATTR) Amyloidosis - Intellia Therapeutics. https:\/\/ir.intelliatx.com\/news-releases\/news-release-details\/intellia-announces-first-clinical-evidence-ongoing-phase-1-study. Accessed 23 Jul 2025."},{"key":"4042_CR117","doi-asserted-by":"publisher","first-page":"396","DOI":"10.1038\/s42003-021-01942-4","volume":"4","author":"H-X Deng","year":"2021","unstructured":"Deng H-X, Zhai H, Shi Y, Liu G, Lowry J, Liu B, et al. Efficacy and long-term safety of CRISPR\/Cas9 genome editing in the SOD1-linked mouse models of ALS. Commun Biol. 2021;4:396.","journal-title":"Commun Biol."},{"key":"4042_CR118","first-page":"50326","volume":"75","author":"SL DeVos","year":"2013","unstructured":"DeVos SL, Miller TM. Direct intraventricular delivery of drugs to the rodent central nervous system. J Vis Exp. 2013;75:50326.","journal-title":"J Vis Exp."},{"key":"4042_CR119","doi-asserted-by":"publisher","DOI":"10.1016\/j.mtbio.2020.100055","volume":"6","author":"GY Wang","year":"2020","unstructured":"Wang GY, Rayner SL, Chung R, Shi BY, Liang XJ. Advances in nanotechnology-based strategies for the treatments of amyotrophic lateral sclerosis. Mater Today Bio. 2020;6:100055.","journal-title":"Mater Today Bio"},{"key":"4042_CR120","doi-asserted-by":"publisher","first-page":"12","DOI":"10.52547\/nl.1.1.12","volume":"1","author":"F Nabizadeh","year":"2022","unstructured":"Nabizadeh F. Biomaterials in the treatment of amyotrophic lateral sclerosis. Neurology Letters. 2022;1:12\u20136.","journal-title":"Neurology Letters"},{"key":"4042_CR121","doi-asserted-by":"publisher","first-page":"1","DOI":"10.2174\/0115672018342513241230061704","volume":"22","author":"N Sharma","year":"2025","unstructured":"Sharma N, Kumar A, Sambhakar S, Bhatia D, Hussain S, Mursal M, et al. Recent advances in nanotherapeutics and theranostics for squamous cell carcinoma: a comprehensive review. Current Drug Deliv. 2025;22:1\u201319.","journal-title":"Current Drug Deliv"},{"issue":"1","key":"4042_CR122","doi-asserted-by":"publisher","first-page":"2","DOI":"10.2174\/1872208317666230320164219","volume":"18","author":"V Kumar","year":"2024","unstructured":"Kumar V, Nair SC. Nano lipid carriers as a promising drug delivery carrier for neurodegenerative disorders - an overview of recent advances. Recent Pat Biotechnol. 2024;18(1):2\u201321.","journal-title":"Recent Pat Biotechnol"},{"key":"4042_CR123","doi-asserted-by":"publisher","first-page":"527","DOI":"10.1515\/tnsci-2022-0258","volume":"13","author":"KR Mittal","year":"2022","unstructured":"Mittal KR, Pharasi N, Sarna B, Singh M, Rachana null, Haider S, et al. Nanotechnology-based drug delivery for the treatment of CNS disorders. Transl Neurosci. 2022;13:527\u201346.","journal-title":"Transl Neurosci"},{"key":"4042_CR124","doi-asserted-by":"publisher","first-page":"443","DOI":"10.3390\/pharmaceutics15020443","volume":"15","author":"T Ili\u0107","year":"2023","unstructured":"Ili\u0107 T, \u0110okovi\u0107 JB, Nikoli\u0107 I, Mitrovi\u0107 JR, Panteli\u0107 I, Savi\u0107 SD, et al. Parenteral Lipid-Based nanoparticles for CNS disorders: integrating various facets of preclinical evaluation towards more effective clinical translation. Pharmaceutics. 2023;15:443.","journal-title":"Pharmaceutics"},{"key":"4042_CR125","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1080\/03639045.2021.2007394","volume":"47","author":"S Srivastava","year":"2021","unstructured":"Srivastava S, Kumar A, Yadav P, Kumar, Mathew J, Chourasia M. Formulation and performance evaluation of polymeric mixed micelles encapsulated with Baicalein for breast cancer treatment. Drug Dev Ind Pharm. 2021;47:1\u201338.","journal-title":"Drug Dev Ind Pharm"},{"key":"4042_CR126","doi-asserted-by":"publisher","first-page":"1819","DOI":"10.2217\/nnm-2021-0468","volume":"17","author":"P Maurya","year":"2022","unstructured":"Maurya P, Saklani R, Singh S, Nisha R, Mishra N, Singh P, et al. Effective uptake of folate-functionalized ethionamide-loaded hybrid system: targeting alveolar macrophages. Nanomedicine. 2022;17:1819\u201331.","journal-title":"Nanomedicine"},{"key":"4042_CR127","doi-asserted-by":"crossref","unstructured":"Kumar A, Dhiman C, Narayan KP, Kumar M, Sharma M, Nanotherapeutics: restoring gut-dysbiosis and inducing cancer apoptosis. Spatially variable genes in cancer: development, progression, and treatment response. IGI Global Scientific Publishing; 2025. pp. 177\u2013204. https:\/\/www.igi-global.com\/chapter\/nanotherapeutics\/www.igi-global.com\/chapter\/nanotherapeutics\/366020. Accessed 15 July 2025.","DOI":"10.4018\/979-8-3693-7728-4.ch007"},{"key":"4042_CR128","doi-asserted-by":"publisher","first-page":"337","DOI":"10.1111\/jcpt.12808","volume":"44","author":"GM Jojo","year":"2019","unstructured":"Jojo GM, Kuppusamy G. Scope of new formulation approaches in the repurposing of Pioglitazone for the management of Alzheimer\u2019s disease. J Clin Pharm Ther. 2019;44:337\u201348.","journal-title":"J Clin Pharm Ther"},{"key":"4042_CR129","doi-asserted-by":"publisher","first-page":"4838","DOI":"10.1021\/acsbiomaterials.2c00865","volume":"8","author":"D D\u00edaz-Garc\u00eda","year":"2022","unstructured":"D\u00edaz-Garc\u00eda D, Ferrer-Donato \u00c1, M\u00e9ndez-Arriaga JM, Cabrera-Pinto M, D\u00edaz-S\u00e1nchez M, Prashar S, et al. Design of mesoporous silica nanoparticles for the treatment of amyotrophic lateral sclerosis (ALS) with a therapeutic cocktail based on leptin and pioglitazone. ACS Biomater Sci Eng. 2022;8:4838\u201349.","journal-title":"ACS Biomater Sci Eng"},{"key":"4042_CR130","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1016\/j.jconrel.2024.11.074","volume":"378","author":"GR Ediriweera","year":"2025","unstructured":"Ediriweera GR, Sivaram AJ, Cowin G, Brown ML, McAlary L, Lum JS, et al. Lipid nanoparticles and transcranial focused ultrasound enhance the delivery of SOD1 antisense oligonucleotides to the murine brain for ALS therapy. J Control Release. 2025;378:221\u201335.","journal-title":"J Control Release."},{"key":"4042_CR131","volume-title":"Liposome-a comprehensive approach for researchers.\u00a0Molecular pharmacology","author":"M Sharma","year":"2020","unstructured":"Sharma M, Joshi J, Chouhan NK, Talati MN, Vaidya S, Kumar A, et al. Liposome-a comprehensive approach for researchers.\u00a0Molecular pharmacology. IntechOpen; 2020."},{"key":"4042_CR132","doi-asserted-by":"publisher","first-page":"356","DOI":"10.1093\/chromsci\/bmad070","volume":"62","author":"A Kumar","year":"2024","unstructured":"Kumar A, Rana R, Saklani R, Kumar M, Yadav PK, Tiwari A, et al. Technology transfer of a validated RP-HPLC method for the simultaneous estimation of Andrographolide and Paclitaxel in application to pharmaceutical nanoformulation. J Chromatogr Sci. 2024;62:356\u201363.","journal-title":"J Chromatogr Sci"},{"key":"4042_CR133","doi-asserted-by":"publisher","DOI":"10.1080\/28378083.2025.2533990","volume":"2","author":"R Singh","year":"2025","unstructured":"Singh R, Kumar A, Srivastava D, Narayan KP, Chaurasia M, Flora SJS. Nano-formulation technology for simultaneous Paclitaxel and Andrographolide delivery: pre-formulation insights. Essential Chem. 2025;2:2533990.","journal-title":"Essential Chem"},{"key":"4042_CR134","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1016\/j.ejps.2018.04.026","volume":"120","author":"T Yang","year":"2018","unstructured":"Yang T, Ferrill L, Gallant L, McGillicuddy S, Fernandes T, Schields N, et al. Verapamil and riluzole cocktail liposomes overcome pharmacoresistance by inhibiting P-glycoprotein in brain endothelial and astrocyte cells: a potent approach to treat amyotrophic lateral sclerosis. Eur J Pharm Sci. 2018;120:30\u20139.","journal-title":"Eur J Pharm Sci"},{"key":"4042_CR135","unstructured":"Tofersen. The ALS Association. https:\/\/www.als.org\/navigating-als\/living-with-als\/fda-approved-drugs\/tofersen. Accessed 15 July 2025."},{"key":"4042_CR136","unstructured":"Orange Book. Approved Drug Products with Therapeutic Equivalence Evaluations. https:\/\/www.accessdata.fda.gov\/scripts\/cder\/ob\/results_product.cfm?Appl_Type=N&Appl_No=215887#42909. Accessed 15 July 2025."},{"key":"4042_CR137","doi-asserted-by":"publisher","first-page":"1043","DOI":"10.1016\/j.tips.2023.08.008","volume":"44","author":"J Jin","year":"2023","unstructured":"Jin J, Zhong X-B. ASO drug Qalsody (tofersen) targets amyotrophic lateral sclerosis. Trends Pharmacol Sci. 2023;44:1043\u20134.","journal-title":"Trends Pharmacol Sci"},{"key":"4042_CR138","doi-asserted-by":"publisher","first-page":"234","DOI":"10.1089\/nat.2023.0027","volume":"33","author":"W van Roon-Mom","year":"2023","unstructured":"van Roon-Mom W, Ferguson C, Aartsma-Rus A. From failure to meet the clinical endpoint to U.S. food and drug administration approval: 15th antisense oligonucleotide therapy approved Qalsody (Tofersen) for treatment of SOD1 mutated amyotrophic lateral sclerosis. Nucleic Acid Ther. 2023;33:234\u20137.","journal-title":"Nucleic Acid Ther"},{"key":"4042_CR139","unstructured":"Research C for DE and. Drug Trials Snapshots: QALSODY; 2024. https:\/\/www.fda.gov\/drugs\/drug-approvals-and-databases\/drug-trials-snapshots-qalsody. Accessed 15 July 2025."},{"key":"4042_CR140","unstructured":"FDA approves QALSODY. \u2122 (tofersen) as the first treatment targeting a genetic cause of ALS: Ionis Pharmaceuticals, Inc. https:\/\/ir.ionis.com\/news-releases\/news-release-details\/fda-approves-qalsodytm-tofersen-first-treatment-targeting. Accessed 15 July 2025."},{"key":"4042_CR141","unstructured":"FDA Grants Accelerated Approval. for QALSODY\u2122 (tofersen) for SOD1-ALS, a Major Scientific Advancement as the First Treatment to Target a Genetic Cause of ALS: Biogen. https:\/\/investors.biogen.com\/news-releases\/news-release-details\/fda-grants-accelerated-approval-qalsodytm-tofersen-sod1-als. Accessed 16 Jul 2025."},{"key":"4042_CR142","doi-asserted-by":"publisher","DOI":"10.1016\/j.eclinm.2024.102495","volume":"69","author":"M Wiesenfarth","year":"2024","unstructured":"Wiesenfarth M, Dorst J, Brenner D, Elmas Z, Parlak \u00d6, Uzelac Z, et al. Effects of Tofersen treatment in patients with SOD1-ALS in a real-world setting - a 12-month multicenter cohort study from the German early access program. EClinicalMedicine. 2024;69:102495.","journal-title":"EClinicalMedicine"},{"key":"4042_CR143","unstructured":"Research C for DE and. Accelerated Approval Program. FDA. FDA; 2024. https:\/\/www.fda.gov\/drugs\/nda-and-bla-approvals\/accelerated-approval-program. Accessed 15 July 2025."},{"key":"4042_CR144","unstructured":"FDA approves first ALS treatment via accelerated approval. The ALS Association. https:\/\/www.als.org\/stories-news\/fda-approves-first-als-treatment-accelerated-approval. Accessed 15 July 2025."},{"key":"4042_CR145","doi-asserted-by":"publisher","first-page":"342","DOI":"10.1159\/000516752","volume":"55","author":"CA Brown","year":"2021","unstructured":"Brown CA, Lally C, Kupelian V, Flanders WD. Estimated prevalence and incidence of amyotrophic lateral sclerosis and SOD1 and C9orf72 genetic variants. Neuroepidemiology. 2021;55:342\u201353.","journal-title":"Neuroepidemiology"},{"key":"4042_CR146","unstructured":"Health Canada accepts for review new drug submission for Tofersen for treatment of rare. genetic form of ALS. https:\/\/www.biogen.ca\/en-ca\/news\/2024-03-11-news.html. Accessed 15 July 2025."},{"key":"4042_CR147","unstructured":"EU\/3\/16\/1732\u2014orphan designation for treatment of amyotrophic lateral sclerosis: European Medicines Agency (EMA). 2016. https:\/\/www.ema.europa.eu\/en\/medicines\/human\/orphan-designations\/eu-3-16-1732. Accessed 16 July 2025."},{"key":"4042_CR148","unstructured":"EU Approves Biogen\u2019s Tofersen as First Treatment for SOD1 ALS. Neurology live; 2024. https:\/\/www.neurologylive.com\/view\/eu-approves-biogen-tofersen-first-treatment-sod1-als. Accessed 15 July 2025."},{"key":"4042_CR149","unstructured":"New treatment for rare motor neurone disease recommended for approval: European Medicines Agency (EMA); 2024. https:\/\/www.ema.europa.eu\/en\/news\/new-treatment-rare-motor-neurone-disease-recommended-approval. Accessed 10 July 2025."},{"key":"4042_CR150","unstructured":"European Medicines Agency Accepts Tofersen Marketing Authorization Application to Treat Rare. Genetic form of ALS: Biogen. https:\/\/investors.biogen.com\/news-releases\/news-release-details\/european-medicines-agency-accepts-tofersen-marketing. Accessed 10 July 2025."},{"key":"4042_CR151","unstructured":"Biogen\u2019s QALSODY\u00ae (tofersen.), the First Therapy to Treat Rare, Genetic Form of ALS, Received Positive Opinion from CHMP: Biogen. https:\/\/investors.biogen.com\/news-releases\/news-release-details\/biogens-qalsodyr-tofersen-first-therapy-treat-rare-genetic-form. Accessed 16 July 2025."},{"key":"4042_CR152","unstructured":"Administration (TGA) TG. Notice for tofersen (Biogen Australia Pty Ltd): Therapeutic Goods Administration (TGA). Therapeutic Goods Administration (TGA); 2025. https:\/\/www.tga.gov.au\/resources\/designations-determinations\/notice-tofersen-biogen-australia-pty-ltd. Accessed 16 July 2025."},{"key":"4042_CR153","unstructured":"Administration (TGA) TG. QALSODY Biogen Australia Pty Ltd: Therapeutic Goods Administration (TGA). Therapeutic Goods Administration (TGA). 2025. https:\/\/www.tga.gov.au\/resources\/prescription-medicines-under-evaluation\/qalsody-biogen-australia-pty-ltd. Accessed 16 Jul 2025."},{"key":"4042_CR154","doi-asserted-by":"publisher","first-page":"4610","DOI":"10.3390\/ijms23094610","volume":"23","author":"J Doroszkiewicz","year":"2022","unstructured":"Doroszkiewicz J, Groblewska M, Mroczko B. Molecular biomarkers and their implications for the early diagnosis of selected neurodegenerative diseases. Int J Mol Sci. 2022;23:4610.","journal-title":"Int J Mol Sci"},{"key":"4042_CR155","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1080\/21541264.2023.2200721","volume":"14","author":"P Sant","year":"2023","unstructured":"Sant P, Rippe K, Mallm J-P. Approaches for single-cell RNA sequencing across tissues and cell types. Transcription. 2023;14:127\u201345.","journal-title":"Transcription"},{"key":"4042_CR156","doi-asserted-by":"publisher","first-page":"657","DOI":"10.1212\/WNL.94.15_supplement.657","volume":"94","author":"M Cudkowicz","year":"2020","unstructured":"Cudkowicz M, Miller T, Shaw P, Bennett CF, Lane R, Chang I, et al. Tofersen, a SOD1 antisense oligonucleotide in participants with ALS\u2014results from a multiple dose study. Neurology. 2020;94:657.","journal-title":"Neurology."},{"key":"4042_CR157","doi-asserted-by":"publisher","first-page":"1913","DOI":"10.2174\/1570180820666230622120759","volume":"21","author":"S Shukla","year":"2024","unstructured":"Shukla S, Tiwari S, Bhattacharya R, Ojha S, Mishra S, Gupta SK. Nanotechnology-based approaches for nose-to-brain drug delivery in neurodegenerative diseases. Lett Drug Des Discovery. 2024;21:1913\u201321.","journal-title":"Lett Drug Des Discovery"},{"key":"4042_CR158","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-023-01481-w","volume":"8","author":"D Wu","year":"2023","unstructured":"Wu D, Chen Q, Chen X, Han F, Chen Z, Wang Y. The blood-brain barrier: structure, regulation, and drug delivery. Signal Transduct Target Ther. 2023;8:217.","journal-title":"Signal Transduct Target Ther"},{"key":"4042_CR159","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1016\/B978-0-323-85544-0.00014-9","volume-title":"Nanomedical drug delivery for neurodegenerative diseases","author":"S Shilpi","year":"2022","unstructured":"Shilpi S, Jain A, Dixit S, Saraogi G, Yadav AK, Jain SK. Chapter 4\u2014Lipid nanocarrier-based drug delivery for the treatment of brain-related disorders. In: Yadav AK, Shukla R, Flora SJS, editors. Nanomedical drug delivery for neurodegenerative diseases. Academic; 2022. p. 55\u201365."}],"container-title":["Orphanet Journal of Rare Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13023-025-04042-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13023-025-04042-2\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13023-025-04042-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T16:04:10Z","timestamp":1763741050000},"score":1,"resource":{"primary":{"URL":"https:\/\/ojrd.biomedcentral.com\/articles\/10.1186\/s13023-025-04042-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,21]]},"references-count":159,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["4042"],"URL":"https:\/\/doi.org\/10.1186\/s13023-025-04042-2","relation":{},"ISSN":["1750-1172"],"issn-type":[{"value":"1750-1172","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,21]]},"assertion":[{"value":"17 June 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 September 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 November 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"All authors have given their consent for publication of this review manuscript.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent of publication"}},{"value":"All authors declare they do not have competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"598"}}