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Direct reprogramming of patient fibroblasts to neuronal progenitor cells and subsequent differentiation into patient astrocytes allows rapid generation of disease relevant cell types. Thus, this methodology can facilitate compound testing in a diverse genetic background resulting in a more representative population for therapeutic evaluation. Here, we used established co\u2010culture assays with motor neurons and reprogrammed patient skin\u2010derived astrocytes (iAs) to evaluate the effects of (SP\u20104\u20102)\u2010[[2,2\u2019\u2010(1,2\u2010dimethyl\u20101,2\u2010ethanediylidene)bis[N\u2010methylhydrazinecarbothioamidato\u2010\u03ba<jats:italic>N<\/jats:italic><jats:sup><jats:italic>2<\/jats:italic><\/jats:sup>,\u03ba<jats:italic>S<\/jats:italic>]](2\u2010)]\u2010copper (CuATSM), currently in clinical trial for ALS in Australia. Pretreatment of iAs with CuATSM had a differential effect on neuronal survival following co\u2010culture with healthy motor neurons. Using this assay, we identified responding and non\u2010responding cell lines for both sporadic and familial ALS (mutant SOD1 and C9ORF72). Importantly, elevated mitochondrial respiration was the common denominator in all CuATSM\u2010responders, a metabolic phenotype not observed in non\u2010responders. Pre\u2010treatment of iAs with CuATSM restored mitochondrial activity to levels comparable to healthy controls. Hence, this metabolic parameter might allow selection of patient subpopulations best suited for CuATSM treatment. Moreover, CuATSM might have additional therapeutic value for mitochondrial disorders. Enhanced understanding of patient\u2010specific cellular and molecular profiles could help improve clinical trial design in the future.<\/jats:p>","DOI":"10.1002\/glia.24278","type":"journal-article","created":{"date-parts":[[2022,10,10]],"date-time":"2022-10-10T13:04:27Z","timestamp":1665407067000},"page":"350-365","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["<scp>CuATSM<\/scp> effectively ameliorates <scp>ALS<\/scp> patient astrocyte\u2010mediated motor neuron toxicity in human in vitro models of amyotrophic lateral sclerosis"],"prefix":"10.1002","volume":"71","author":[{"given":"Cassandra N.","family":"Dennys","sequence":"first","affiliation":[{"name":"Center for Gene Therapy The Abigail Wexner Research Institute at Nationwide Children's Hospital  Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florence","family":"Roussel","sequence":"additional","affiliation":[{"name":"Center for Gene Therapy The Abigail Wexner Research Institute at Nationwide Children's Hospital  Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9683-6280","authenticated-orcid":false,"given":"Rochelle","family":"Rodrigo","sequence":"additional","affiliation":[{"name":"Center for Gene Therapy The Abigail Wexner Research Institute at Nationwide Children's Hospital  Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaojin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Center for Gene Therapy The Abigail Wexner Research Institute at Nationwide Children's Hospital  Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Sierra Delgado","sequence":"additional","affiliation":[{"name":"Center for Gene Therapy The Abigail Wexner Research Institute at Nationwide Children's Hospital  Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annalisa","family":"Hartlaub","sequence":"additional","affiliation":[{"name":"Center for Gene Therapy The Abigail Wexner Research Institute at Nationwide Children's Hospital  Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asya","family":"Saelim\u2010Ector","sequence":"additional","affiliation":[{"name":"Center for Gene Therapy The Abigail Wexner Research Institute at Nationwide Children's Hospital  Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Will","family":"Ray","sequence":"additional","affiliation":[{"name":"Mathematics Department The Abigail Wexner Research Institute at Nationwide Children's Hospital  Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Heintzman","sequence":"additional","affiliation":[{"name":"Department of Neurology The Ohio State University Medical Center  Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashley","family":"Fox","sequence":"additional","affiliation":[{"name":"Department of Neurology The Ohio State University Medical Center  Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen J.","family":"Kolb","sequence":"additional","affiliation":[{"name":"Department of Neurology The Ohio State University Medical Center  Columbus Ohio USA"},{"name":"Department of Biological Chemistry &amp; 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