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This homology allows robust insights to be gained into pathophysiologic mechanisms and therapeutic targets for the heterogeneous class of primary mitochondrial diseases (PMDs) through the study of diverse in vitro cellular and in vivo animal models. Dramatic advances in genetic technologies, ranging from RNA interference to achieve graded knock\u2010down of gene expression to CRISPR\/Cas\u2010based gene editing that yields a stable gene knock\u2010out or targeted mutation knock\u2010in, have enabled the ready establishment of mitochondrial disease models for a plethora of individual nuclear gene disorders. These models are complemented and extended by the use of pharmacologic inhibitor\u2010based stressors to characterize variable degrees, onset, duration, and combinations of acute on chronic mitochondrial dysfunction in individual respiratory chain enzyme complexes or distinct biochemical pathways within mitochondria. Herein is described the rationale for, and progress made in, \u201ctherapeutic cross\u2010training,\u201d a novel approach meant to improve the validity and rigor of experimental conclusions when testing therapies by studying treatment effects in multiple, evolutionarily\u2010distinct species, including\n                    <jats:italic>Caenorhabditis elegans<\/jats:italic>\n                    (invertebrate, worm),\n                    <jats:italic>Danio rerio<\/jats:italic>\n                    (vertebrate, zebrafish),\n                    <jats:italic>Mus musculus<\/jats:italic>\n                    (mammal, mouse), and\/or human patient primary fibroblast cell line models of PMD. The goal of these preclinical studies is to identify lead therapies from candidate molecules or library screens that consistently demonstrate efficacy, with minimal toxicity, in specific subtypes of mitochondrial disease. Conservation of in vitro and in vivo therapeutic effects of lead molecules across species has proven extensive, where molar concentrations found to be toxic or efficacious in one species are often consistent with therapeutic effects at similar doses seen in other mitochondrial disease models. Phenotypic outcome studies in all models are prioritized at the level of survival and function, to reflect the ultimate goal of developing highly potent therapies for human mitochondrial disease. Lead compounds that demonstrate significant benefit on gross phenotypes may be further scrutinized in these same models to decipher their cellular targets, mechanism(s), and detailed biochemical effects. High\u2010throughput, automated technologic advances will be discussed that enable efficient, parallel screening in a diverse array of mitochondrial disease disorders and overarching subclasses of compounds, concentrations, libraries, and combinations. Overall, this therapeutic cross\u2010training approach has proven valuable to identify compounds with optimal potency and safety profiles among major biochemical subtypes or specific genetic etiologies of mitochondrial disease. This approach further supports rational prioritization of lead compounds, target concentrations, and specific disease phenotypes, outcomes, and subgroups to optimally inform the design of clinical trials that test their efficacy in human mitochondrial disease subjects.\n                  <\/jats:p>","DOI":"10.1002\/jimd.12319","type":"journal-article","created":{"date-parts":[[2020,10,2]],"date-time":"2020-10-02T09:55:26Z","timestamp":1601632526000},"page":"312-324","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["The pursuit of precision mitochondrial medicine: Harnessing preclinical cellular and animal models to optimize mitochondrial disease therapeutic discovery"],"prefix":"10.1002","volume":"44","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1723-6728","authenticated-orcid":false,"given":"Marni J.","family":"Falk","sequence":"first","affiliation":[{"name":"Mitochondrial Medicine Frontier Program, Division of Human Genetics, Department of Pediatrics The Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine  Philadelphia Pennsylvania USA"},{"name":"Department of Pediatrics University of Pennsylvania Perelman School of Medicine  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,11,2]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(18)30727-X"},{"key":"e_1_2_7_3_1","volume-title":"Mitochondrial Disease Genes Compendium: From Genes to Clinical Manifestations","author":"Falk MJ","year":"2020"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.R117.809194"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biocel.2014.02.012"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0069282"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2016.80"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-1978-5"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2477-4"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-019-0017-4"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcdb.2016.02.011"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-981-13-8367-0_14"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1097\/WCO.0000000000000646"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mito.2015.02.005"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1097\/MOP.0000000000000954"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11940-009-0046-0"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2018.02.013"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddv207"},{"key":"e_1_2_7_19_1","first-page":"24","volume-title":"Book Nutritional Inadequacies in Mitochondrial\u2010associated Metabolic Disorders","author":"Falk MJ","year":"2018"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pathol-020117-043644"},{"key":"e_1_2_7_21_1","article-title":"Treatment for mitochondrial disorders","volume":"4","author":"Pfeffer G","year":"2012","journal-title":"Cochrane Database Syst Rev"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.200802092"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1258096"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2013.12.011"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuint.2017.07.008"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/ddrr.114"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1093\/femsyr\/foy040"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/bs.ctdb.2016.07.001"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddz023"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10545-016-9986-1"},{"key":"e_1_2_7_31_1","volume-title":"FDA Memorandum: Critical Path Innovation Meeting Regarding Drug Development for Mitochondrial Diseases","author":"Center for Drug Evaluation and Research, Office of Translational Sciences, Food and Drug Administration","year":"2015"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.2174\/1568026617666170131114401"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd4627"},{"key":"e_1_2_7_34_1","first-page":"37","volume-title":"Enabling Precision Medicine. 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