{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T20:01:21Z","timestamp":1792008081154,"version":"4.4.0"},"reference-count":44,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2025,7,23]],"date-time":"2025-07-23T00:00:00Z","timestamp":1753228800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that primarily affects motor neurons, leading to loss of muscle control, and, ultimately, respiratory failure and death. Despite some advances in recent years, the underlying genetic and molecular mechanisms of ALS remain largely elusive. In this respect, a better understanding of these mechanisms is needed to identify new and biologically relevant therapeutic targets that could be developed into treatments that are truly disease-modifying, in that they address the underlying causes rather than the symptoms of ALS. In this study, we used two approaches to model multi-omics data in order to map and elucidate the genetic and molecular mechanisms involved in ALS, i.e., the molecular landscape building approach and the Patrimony platform. These two methods are complementary because they rely upon different omics data sets, analytic methods, and scoring systems to identify and rank therapeutic target candidates. The orthogonal combination of the two modeling approaches led to significant convergences, as well as some complementarity, both for validating existing therapeutic targets and identifying novel targets. As for validating existing targets, we found that, out of 217 different targets that have been or are being investigated for drug development, 10 have high scores in both the landscape and Patrimony models, suggesting that they are highly relevant for ALS. Moreover, through both models, we identified or corroborated novel putative drug targets for ALS. A notable example of such a target is MATR3, a protein that has strong genetic, molecular, and functional links with ALS pathology. In conclusion, by using two distinct and highly complementary disease modeling approaches, this study enhances our understanding of ALS pathogenesis and provides a framework for prioritizing new therapeutic targets. Moreover, our findings underscore the potential of leveraging multi-omics analyses to improve target discovery and accelerate the development of effective treatments for ALS, and potentially other related complex human diseases.<\/jats:p>","DOI":"10.3390\/ijms26157087","type":"journal-article","created":{"date-parts":[[2025,7,23]],"date-time":"2025-07-23T10:49:17Z","timestamp":1753267757000},"page":"7087","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Identifying Therapeutic Targets for Amyotrophic Lateral Sclerosis Through Modeling of Multi-Omics Data"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9135-4116","authenticated-orcid":false,"given":"Fran\u00e7ois Xavier","family":"Blaudin de Th\u00e9","sequence":"first","affiliation":[{"name":"Servier Research & Development, 91190 Saclay, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cornelius J. H. M.","family":"Klemann","sequence":"additional","affiliation":[{"name":"Donders Institute for Brain, Cognition and Behaviour, Radboud University, 6525 EN Nijmegen, The Netherlands"},{"name":"Department of Medical Neuroscience, Radboud University Medical Center, 6525 EN Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ward","family":"De Witte","sequence":"additional","affiliation":[{"name":"Donders Institute for Brain, Cognition and Behaviour, Radboud University, 6525 EN Nijmegen, The Netherlands"},{"name":"Department of Medical Neuroscience, Radboud University Medical Center, 6525 EN Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanna","family":"Widomska","sequence":"additional","affiliation":[{"name":"Donders Institute for Brain, Cognition and Behaviour, Radboud University, 6525 EN Nijmegen, The Netherlands"},{"name":"Department of Medical Neuroscience, Radboud University Medical Center, 6525 EN Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippe","family":"Delagrange","sequence":"additional","affiliation":[{"name":"Servier Research & Development, 91190 Saclay, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clotilde","family":"Mannoury La Cour","sequence":"additional","affiliation":[{"name":"Servier Research & Development, 91190 Saclay, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4514-5265","authenticated-orcid":false,"given":"M\u00e9lanie","family":"Fouesnard","sequence":"additional","affiliation":[{"name":"Servier Data Factory, 92284 Suresnes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sahar","family":"Elouej","sequence":"additional","affiliation":[{"name":"Servier Research & Development, 91190 Saclay, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keith","family":"Mayl","sequence":"additional","affiliation":[{"name":"Servier Research & Development, 91190 Saclay, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas","family":"L\u00e9vy","sequence":"additional","affiliation":[{"name":"Servier Research & Development, 91190 Saclay, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes","family":"Krupp","sequence":"additional","affiliation":[{"name":"Servier Research & Development, 91190 Saclay, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ross","family":"Jeggo","sequence":"additional","affiliation":[{"name":"Servier Research & Development, 91190 Saclay, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippe","family":"Moingeon","sequence":"additional","affiliation":[{"name":"Servier Research & Development, 91190 Saclay, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geert","family":"Poelmans","sequence":"additional","affiliation":[{"name":"Donders Institute for Brain, Cognition and Behaviour, Radboud University, 6525 EN Nijmegen, The Netherlands"},{"name":"Department of Medical Neuroscience, Radboud University Medical Center, 6525 EN Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1363","DOI":"10.1016\/S0140-6736(22)01272-7","article-title":"Amyotrophic lateral sclerosis","volume":"400","author":"Feldman","year":"2022","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1038\/s41576-023-00592-y","article-title":"Amyotrophic lateral sclerosis: Translating genetic discoveries into therapies","volume":"24","author":"Lopez","year":"2023","journal-title":"Nat. Rev. Genet."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1111\/bpa.12485","article-title":"Integrated molecular landscape of amyotrophic lateral sclerosis provides insights into disease etiology","volume":"28","author":"Klemann","year":"2018","journal-title":"Brain Pathol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.1007\/s40265-023-01904-6","article-title":"Tofersen: First Approval","volume":"83","author":"Blair","year":"2023","journal-title":"Drugs"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1948","DOI":"10.1002\/acn3.51887","article-title":"Therapeutic targeting of ALS pathways: Refocusing an incomplete picture","volume":"10","author":"Maragakis","year":"2023","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1038\/s41573-022-00612-2","article-title":"Amyotrophic lateral sclerosis: A neurodegenerative disorder poised for successful therapeutic translation","volume":"22","author":"Mead","year":"2023","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1636","DOI":"10.1038\/s41588-021-00973-1","article-title":"Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology","volume":"53","author":"Bakker","year":"2021","journal-title":"Nat. Genet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1267","DOI":"10.1016\/j.neuron.2018.02.027","article-title":"Genome-wide Analyses Identify KIF5A as a Novel ALS Gene","volume":"97","author":"Nicolas","year":"2018","journal-title":"Neuron"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1007\/s00401-013-1125-6","article-title":"Protein aggregation in amyotrophic lateral sclerosis","volume":"125","author":"Blokhuis","year":"2013","journal-title":"Acta Neuropathol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1186\/s13024-020-00397-1","article-title":"The role of TDP-43 mislocalization in amyotrophic lateral sclerosis","volume":"15","author":"Suk","year":"2020","journal-title":"Mol. Neurodegener."},{"key":"ref_11","first-page":"CD001447","article-title":"Riluzole for amyotrophic lateral sclerosis (ALS)\/motor neuron disease (MND)","volume":"2012","author":"Miller","year":"2012","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1002\/med.21528","article-title":"Riluzole and edaravone: A tale of two amyotrophic lateral sclerosis drugs","volume":"39","author":"Jaiswa","year":"2019","journal-title":"Med. Res. Rev."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Santos, J.R., and Park, J. (2024). MATR3\u2019s Role beyond the Nuclear Matrix: From Gene Regulation to Its Implications in Amyotrophic Lateral Sclerosis and Other Diseases. Cells, 13.","DOI":"10.3390\/cells13110980"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1038\/nn.3688","article-title":"Mutations in the Matrin 3 gene cause familial amyotrophic lateral sclerosis","volume":"17","author":"Italsgen","year":"2014","journal-title":"Nat. Neurosci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1016\/j.ajpath.2017.10.007","article-title":"Matrin 3 is a Component of Neuronal Cytoplasmic Inclusions of Motor Neurons in Sporadic Amyotrophic Lateral Sclerosis","volume":"188","author":"Tada","year":"2018","journal-title":"Am. J. Pathol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2006.e1","DOI":"10.1016\/j.neurobiolaging.2015.02.017","article-title":"Stratified gene expression analysis identifies major amyotrophic lateral sclerosis genes","volume":"36","author":"Jones","year":"2015","journal-title":"Neurobiol. Aging"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1385","DOI":"10.1002\/jcsm.12945","article-title":"Muscle cells of sporadic amyotrophic lateral sclerosis patients secrete neurotoxic vesicles","volume":"13","author":"Duddy","year":"2022","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"5304","DOI":"10.1038\/s41467-020-18949-w","article-title":"Selective neuronal degeneration in MATR3 S85C knock-in mouse model of early-stage ALS","volume":"11","author":"Kao","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"You, J., Maksimovic, K., Lee, J., Khan, M., Masuda, R., and Park, J. (2022). Selective Loss of MATR3 in Spinal Interneurons, Upper Motor Neurons and Hippocampal CA1 Neurons in a MATR3 S85C Knock-In Mouse Model of Amyotrophic Lateral Sclerosis. Biology, 11.","DOI":"10.3390\/biology11020298"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1002\/path.5289","article-title":"Mutant MATR3 mouse model to explain multisystem proteinopathy","volume":"249","author":"Zhang","year":"2019","journal-title":"J. Pathol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Salem, A., Wilson, C.J., Rutledge, B.S., Dilliott, A., Farhan, S., Choy, W.-Y., and Duennwald, M.L. (2022). Matrin3: Disorder and ALS Pathogenesis. Front. Mol. Biosci., 8.","DOI":"10.3389\/fmolb.2021.794646"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e2206217120","DOI":"10.1073\/pnas.2206217120","article-title":"Neuronal activity regulates Matrin 3 abundance and function in a calcium-dependent manner through calpain-mediated cleavage and calmodulin binding","volume":"120","author":"Malik","year":"2023","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1152\/jn.00417.2016","article-title":"The cerebellum contributes to proprioception during motion","volume":"118","author":"Weeks","year":"2017","journal-title":"J. Neurophysiol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Akay, T., and Murray, A.J. (2021). Relative Contribution of Proprioceptive and Vestibular Sensory Systems to Locomotion: Opportunities for Discovery in the Age of Molecular Science. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22031467"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"103756","DOI":"10.1016\/j.mcn.2022.103756","article-title":"Hyperactivity of Purkinje cell and motor deficits in C9orf72 knockout mice","volume":"121","author":"Liu","year":"2022","journal-title":"Mol. Cell. Neurosci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2335","DOI":"10.4103\/1673-5374.336139","article-title":"Cerebellar pathology in motor neuron disease: Neuroplasticity and neurodegeneration","volume":"17","author":"Chipika","year":"2022","journal-title":"Neural Regen. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.1136\/jnnp-2021-326854","article-title":"Genotype-associated cerebellar profiles in ALS: Focal cerebellar pathology and cerebro-cerebellar connectivity alterations","volume":"92","author":"Bede","year":"2021","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Tan, R.H., Devenney, E., Dobson-Stone, C., Kwok, J.B., Hodges, J.R., Kiernan, M.C., Halliday, G.M., Hornberger, M., and Kassubek, J. (2014). Cerebellar Integrity in the Amyotrophic Lateral Sclerosis\u2014Frontotemporal Dementia Continuum. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0105632"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1016\/j.trecan.2024.07.002","article-title":"Bispecific antibodies: Advancing precision oncology","volume":"10","author":"Herrera","year":"2024","journal-title":"Trends Cancer"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1038\/s41392-022-00947-7","article-title":"Antibody drug conjugate: The \u201cbiological missile\u201d for targeted cancer therapy","volume":"7","author":"Fu","year":"2022","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1038\/s41531-017-0015-3","article-title":"Integrated molecular landscape of Parkinson\u2019s disease","volume":"3","author":"Klemann","year":"2017","journal-title":"NPJ Parkinson Dis."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Widomska, J., De Witte, W., Buitelaar, J.K., Glennon, J.C., and Poelmans, G. (2023). Molecular Landscape of Tourette\u2019s Disorder. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24021428"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Kluivers, K.B., Lince, S.L., Ruiz-Zapata, A.M., Post, W.M., Cartwright, R., Kerkhof, M.H., Widomska, J., De Witte, W., Pecanka, J., and Kiemeney, L.A. (2023). Molecular Landscape of Pelvic Organ Prolapse Provides Insights into Disease Etiology. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24076087"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1186\/s13195-024-01609-2","article-title":"Molecular landscape of the overlap between Alzheimer\u2019s disease and somatic insulin-related diseases","volume":"16","author":"Ruisch","year":"2024","journal-title":"Alzheimer Res. Ther."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"de Leeuw, C.A., Mooij, J.M., Heskes, T., and Posthuma, D. (2015). MAGMA: Generalized Gene-Set Analysis of GWAS Data. PLoS Comput. Biol., 11.","DOI":"10.1371\/journal.pcbi.1004219"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1826","DOI":"10.1038\/s41467-017-01261-5","article-title":"Functional mapping and annotation of genetic associations with FUMA","volume":"8","author":"Watanabe","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"D1074","DOI":"10.1093\/nar\/gkx1037","article-title":"DrugBank 5.0: A major update to the DrugBank database for 2018","volume":"46","author":"Wishart","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"D833","DOI":"10.1093\/nar\/gkw943","article-title":"DisGeNET: A comprehensive platform integrating information on human disease-associated genes and variants","volume":"45","author":"Pinero","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"D605","DOI":"10.1093\/nar\/gkaa1074","article-title":"The STRING database in 2021: Customizable protein-protein networks, and functional characterization of user-uploaded gene\/measurement sets","volume":"49","author":"Szklarczyk","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1016\/j.tips.2023.04.005","article-title":"Artificial intelligence-driven drug development against autoimmune diseases","volume":"44","author":"Moingeon","year":"2023","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1002\/jrsm.1346","article-title":"Meta-analysis and Mendelian randomization: A review","volume":"10","author":"Bowden","year":"2019","journal-title":"Res. Synth. Methods"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"D326","DOI":"10.1093\/nar\/gkab997","article-title":"RNAInter v4.0: RNA interactome repository with redefined confidence scoring system and improved accessibility","volume":"50","author":"Kang","year":"2022","journal-title":"Nucleic Acids Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1038\/nrg2918","article-title":"Network medicine: A network-based approach to human disease","volume":"12","author":"Gulbahce","year":"2011","journal-title":"Nat. Rev. Genet."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"103772","DOI":"10.1016\/j.drudis.2023.103772","article-title":"Transforming drug discovery with a high-throughput AI-powered platform: A 5-year experience with Patrimony","volume":"28","author":"Baudier","year":"2023","journal-title":"Drug Discov. Today"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/15\/7087\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:14:31Z","timestamp":1760033671000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/15\/7087"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,23]]},"references-count":44,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2025,8]]}},"alternative-id":["ijms26157087"],"URL":"https:\/\/doi.org\/10.3390\/ijms26157087","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,23]]}}}