{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T01:06:20Z","timestamp":1779930380130,"version":"3.53.1"},"reference-count":72,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2025,2,19]],"date-time":"2025-02-19T00:00:00Z","timestamp":1739923200000},"content-version":"vor","delay-in-days":18,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100007660","name":"Universiteit Antwerpen","doi-asserted-by":"publisher","award":["38694"],"award-info":[{"award-number":["38694"]}],"id":[{"id":"10.13039\/501100007660","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100013465","name":"French Muscular Dystrophy Association","doi-asserted-by":"publisher","award":["21533"],"award-info":[{"award-number":["21533"]}],"id":[{"id":"10.13039\/100013465","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Gene Medicine"],"published-print":{"date-parts":[[2025,2]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Missense mutations in the <jats:italic>HSPB8<\/jats:italic> gene, encoding the small heat shock protein B8, cause distal hereditary motor neuropathy (dHMN) or an axonal form of Charcot\u2013Marie\u2013Tooth disease (CMT subtype 2L). Mice expressing mutant Hspb8 (Lys141Asn) mimic the human disease, whereas mice lacking Hspb8 show no overt phenotype. We aimed to design an RNA interference treatment strategy that rescues the mutant HSPB8 neuronal and muscle phenotype in patient\u2010derived motor neurons and in a knock\u2010in mouse model of CMT2L\/dHMN.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We optimized RNA interference sequences targeting both human <jats:italic>HSPB8<\/jats:italic> and mouse <jats:italic>HspB8<\/jats:italic> transcripts with the aim to alleviate disease symptoms. We used human induced pluripotent stem cells and the Hspb8 knock\u2010in mouse model. We designed lenti\u2010 and adeno\u2010associated viral vectors that contained the short\u2010hairpin RNA constructs. We performed expression and microscopy studies, magnetic resonance imaging, behaviour analysis and electrophysiology.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In CMT2L patient\u2010derived induced pluripotent stem cells differentiated towards motor neurons, reducing the HSPB8 expression with a short\u2010hairpin RNA (shRNA), directed towards the 3\u2032 untranslated region (3\u2032UTR), ameliorated the morphology and fragmentation of mitochondria. The AAV9\u2010mediated treatment of the 3\u2032UTR shRNA construct, under neuron\u2010specific regulation, in Hspb8 knock\u2010in mice showed inconclusive results towards functional improvement upon expression studies, magnetic resonance imaging and neuropathological findings.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Given the limited beneficial effect of the treatment, the RNA interference\u2013mediated reduction of <jats:italic>HSPB8<\/jats:italic>\/<jats:italic>Hspb8<\/jats:italic> expression might not be the best therapeutic strategy to treat dHMN\/CMT2L, unless a higher viral load and earlier treatment can be applied to the mouse model.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jgm.70013","type":"journal-article","created":{"date-parts":[[2025,2,20]],"date-time":"2025-02-20T05:40:50Z","timestamp":1740030050000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["RNA Interference Targeting Small Heat Shock Protein B8 Failed to Improve Distal Hereditary Motor Neuropathy in the Mouse Model"],"prefix":"10.1002","volume":"27","author":[{"given":"Leen","family":"Vendredy","sequence":"first","affiliation":[{"name":"Peripheral Neuropathy Research Group, Department of Biomedical Sciences University of Antwerp  Antwerp Belgium"},{"name":"Laboratory of Neuromuscular Pathology, Institute Born Bunge University of Antwerp  Antwerp Belgium"},{"name":"\u03bcNEURO Research Centre of Excellence University of Antwerp  Antwerp Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vicky","family":"De\u00a0Winter","sequence":"additional","affiliation":[{"name":"Peripheral Neuropathy Research Group, Department of Biomedical Sciences University of Antwerp  Antwerp Belgium"},{"name":"Laboratory of Neuromuscular Pathology, Institute Born Bunge University of Antwerp  Antwerp Belgium"},{"name":"\u03bcNEURO Research Centre of Excellence University of Antwerp  Antwerp Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonas","family":"Van\u00a0Lent","sequence":"additional","affiliation":[{"name":"Peripheral Neuropathy Research Group, Department of Biomedical Sciences University of Antwerp  Antwerp Belgium"},{"name":"Laboratory of Neuromuscular Pathology, Institute Born Bunge University of Antwerp  Antwerp Belgium"},{"name":"\u03bcNEURO Research Centre of Excellence University of Antwerp  Antwerp Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jasmien","family":"Orije","sequence":"additional","affiliation":[{"name":"\u03bcNEURO Research Centre of Excellence University of Antwerp  Antwerp Belgium"},{"name":"Bio\u2010Imaging, Department of Biomedical Sciences University of Antwerp  Antwerp Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatiana\u00a0Da\u00a0Silva","family":"Authier","sequence":"additional","affiliation":[{"name":"Peripheral Neuropathy Research Group, Department of Biomedical Sciences University of Antwerp  Antwerp Belgium"},{"name":"Laboratory of Neuromuscular Pathology, Institute Born Bunge University of Antwerp  Antwerp Belgium"},{"name":"\u03bcNEURO Research Centre of Excellence University of Antwerp  Antwerp Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Istvan","family":"Katona","sequence":"additional","affiliation":[{"name":"Institute of Neuropathology RWTH Aachen University Hospital  Aachen Germany"},{"name":"Department of Neurology The Houston Methodist Research Institute  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bob","family":"Asselbergh","sequence":"additional","affiliation":[{"name":"Neuromics Support Facility, VIB Center for Molecular Neurology VIB  Antwerp Belgium"},{"name":"Neuromics Support Facility, Department of Biomedical Sciences University of Antwerp  Antwerp Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elias","family":"Adriaenssens","sequence":"additional","affiliation":[{"name":"Peripheral Neuropathy Research Group, Department of Biomedical Sciences University of Antwerp  Antwerp Belgium"},{"name":"Laboratory of Neuromuscular Pathology, Institute Born Bunge University of Antwerp  Antwerp Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joachim","family":"Weis","sequence":"additional","affiliation":[{"name":"Institute of Neuropathology RWTH Aachen University Hospital  Aachen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marleen","family":"Verhoye","sequence":"additional","affiliation":[{"name":"\u03bcNEURO Research Centre of Excellence University of Antwerp  Antwerp Belgium"},{"name":"Bio\u2010Imaging, Department of Biomedical Sciences University of Antwerp  Antwerp Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2162-0933","authenticated-orcid":false,"given":"Vincent","family":"Timmerman","sequence":"additional","affiliation":[{"name":"Peripheral Neuropathy Research Group, Department of Biomedical Sciences University of Antwerp  Antwerp Belgium"},{"name":"Laboratory of Neuromuscular Pathology, Institute Born Bunge University of Antwerp  Antwerp Belgium"},{"name":"\u03bcNEURO Research Centre of Excellence University of Antwerp  Antwerp Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,2,19]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng1328"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-004-1218-3"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000002324"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2022.2160564"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddq257"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1042\/BST20130118"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.127498"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M706304200"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2009.11.022"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2016.04.007"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep22827"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2016.07.021"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.4161\/auto.5.3.7894"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M807440200"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1005582"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-017-1756-0"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2016.11.013"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/dvg.20319"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0158644"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/0471142727.mb2801s70"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/0378-1119(88)90354-X"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awab226"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-00911-y"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2007-8-2-r19"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2019"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2089"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.2144\/000112203"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbiotec.2013.11.004"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/gt.2010.179"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/0014-2999(80)90515-4"},{"issue":"5","key":"e_1_2_10_32_1","first-page":"1413","article-title":"Epidural and Intrathecal Drug Delivery in Rats and Mice for Experimental Research: Fundamental Concepts, Techniques, Precaution, and Application","volume":"11","author":"Rahman M. M.","year":"2023","journal-title":"Biomedicine"},{"key":"e_1_2_10_33_1","article-title":"In Vivo Electrophysiological Measurement of Compound Muscle Action Potential From the Forelimbs in Mouse Models of Motor Neuron Degeneration","volume":"136","author":"Pollari E.","year":"2018","journal-title":"Journal of Visualized Experiments"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0147669"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2019.116137"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awr283"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2017.00402"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.abb.2011.06.014"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.23189"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2017.00177"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1261\/rna.1062908"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0801775105"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.1481"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng1650"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0506306102"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtm.2018.12.013"},{"key":"e_1_2_10_47_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.mt.6300394"},{"key":"e_1_2_10_48_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-021-00487-6"},{"key":"e_1_2_10_49_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41434-021-00250-0"},{"key":"e_1_2_10_50_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddy056"},{"key":"e_1_2_10_51_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddz199"},{"key":"e_1_2_10_52_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1522202113"},{"key":"e_1_2_10_53_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2019.02.017"},{"key":"e_1_2_10_54_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2020.135357"},{"key":"e_1_2_10_55_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.1500078"},{"key":"e_1_2_10_56_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awz064"},{"key":"e_1_2_10_57_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI137159"},{"key":"e_1_2_10_58_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-22593-3"},{"key":"e_1_2_10_59_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI130600"},{"key":"e_1_2_10_60_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-018-0224-7"},{"key":"e_1_2_10_61_1","doi-asserted-by":"publisher","DOI":"10.1002\/glia.20620"},{"key":"e_1_2_10_62_1","doi-asserted-by":"publisher","DOI":"10.1097\/NEN.0b013e3181d1e60f"},{"key":"e_1_2_10_63_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddt659"},{"key":"e_1_2_10_64_1","doi-asserted-by":"publisher","DOI":"10.1093\/jnen\/nlw004"},{"key":"e_1_2_10_65_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1762-15.2016"},{"key":"e_1_2_10_66_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms19124072"},{"key":"e_1_2_10_67_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-20081-1"},{"key":"e_1_2_10_68_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0231600"},{"key":"e_1_2_10_69_1","first-page":"1","article-title":"Generation of Human Motor Units With Functional Neuromuscular Junctions in Microfluidic Devices","volume":"175","author":"Stoklund Dittlau K.","year":"2021","journal-title":"Journal of Visualized Experiments"},{"key":"e_1_2_10_70_1","doi-asserted-by":"publisher","DOI":"10.1038\/s12276-024-01250-x"},{"key":"e_1_2_10_71_1","doi-asserted-by":"publisher","DOI":"10.1038\/s42003-021-01839-2"},{"key":"e_1_2_10_72_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12192-020-01101-4"},{"key":"e_1_2_10_73_1","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2024.2439649"}],"container-title":["The Journal of Gene Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jgm.70013","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,12]],"date-time":"2025-03-12T01:21:37Z","timestamp":1741742497000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/jgm.70013"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2]]},"references-count":72,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2025,2]]}},"alternative-id":["10.1002\/jgm.70013"],"URL":"https:\/\/doi.org\/10.1002\/jgm.70013","archive":["Portico"],"relation":{},"ISSN":["1099-498X","1521-2254"],"issn-type":[{"value":"1099-498X","type":"print"},{"value":"1521-2254","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2]]},"assertion":[{"value":"2024-10-04","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-02-08","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-02-19","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70013"}}