{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T19:48:44Z","timestamp":1790279324980,"version":"4.1.0"},"reference-count":65,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2025,12,8]],"date-time":"2025-12-08T00:00:00Z","timestamp":1765152000000},"content-version":"vor","delay-in-days":7,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T00:00:00Z","timestamp":1764547200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100005202","name":"Muscular Dystrophy Association","doi-asserted-by":"publisher","award":["1297770"],"award-info":[{"award-number":["1297770"]}],"id":[{"id":"10.13039\/100005202","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical &amp;amp; Translational Med"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Valosin\u2010containing protein (VCP) related disease, also known as multisystem proteinopathy 1 (MSP1), is an autosomal dominant disease caused by gain\u2010of\u2010function pathogenic variants of the\n                      <jats:italic>VCP<\/jats:italic>\n                      gene. The disease presents with variable combinations of inclusion body myopathy, early\u2010onset Paget's disease of bone, frontotemporal dementia and may also overlap with familial amyotrophic lateral sclerosis. There is currently no treatment for this progressive disease associated with early demise resulting from proximal limb girdle and respiratory muscle weakness. We hypothesise that regulating VCP hyperactivity to normal levels can reduce the disease pathology.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Main topics covered<\/jats:title>\n                    <jats:p>\n                      In this study, we assessed the effect of antisense oligonucleotides (ASOs) specifically targeting the human\n                      <jats:italic>VCP<\/jats:italic>\n                      gene in the patient (R155H) iPSC\u2010derived skeletal muscle progenitor cells (SMPCs). ASOs were well tolerated up to a concentration of 5\u00a0\u00b5M and significantly reduced VCP protein expression in the SMPCs by 48% (95% CI [39\u201356]). We also treated the transgenic mouse model of VCP disease with the overexpressed humanised VCP severe A232E pathogenic gene variant (VCP A232E mice) with weekly subcutaneous ASO injections starting from 6 months of age for 3 months. In the skeletal muscle of transgenic mice, ASOs resulted in 30% (95% CI [27\u201332]) knockdown of VCP protein compared with control ASO. The ASO\u2010mediated reduction of VCP expression in muscle tissue was associated with improvement in autophagy flux and reduction in TAR DNA binding protein 43 (TDP\u201043) expression, hallmarks of VCP related MSP1. In addition, ASO\u2010treated VCP A232E mice showed improvements in functional tests of muscle strength, such as rotarod and inverted screen test compared with mice treated with control ASO.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These results suggest that targeting VCP could be beneficial in preventing the progression of the VCP myopathy and hold promise for the treatment of patients with VCP related MSP1.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key points<\/jats:title>\n                    <jats:p>\n                      <jats:list>\n                        <jats:list-item>\n                          <jats:p>VCP multisystem proteinopathy 1 is caused by gain\u2010of\u2010function pathogenic variants of the VCP gene.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>VCP targeting ASOs were well tolerated and significantly reduced VCP, TAR DNA binding protein 43 (TDP 43), and autophagy protein expression in the (R155H) iPSC\u2010derived skeletal muscle progenitor cells (SMPCs).<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>The ASOs reduced VCP, TDP\u201043, and autophagy flux expression, and improved functional tests of muscle strength in the humanized VCP A232E mice.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ctm2.70530","type":"journal-article","created":{"date-parts":[[2025,12,8]],"date-time":"2025-12-08T10:19:51Z","timestamp":1765189191000},"source":"Crossref","is-referenced-by-count":3,"title":["Antisense oligonucleotides targeting valosin\u2010containing protein ameliorate muscle pathology and molecular defects in cell and mouse models of multisystem proteinopathy"],"prefix":"10.1002","volume":"15","author":[{"given":"Pallabi","family":"Pal","sequence":"first","affiliation":[{"name":"Department of Pediatrics Division of Genetics and Genomic Medicine University of California  Irvine California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michele","family":"Carrer","sequence":"additional","affiliation":[{"name":"Ionis Pharmaceuticals, Inc.  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