{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T19:44:24Z","timestamp":1777923864494,"version":"3.51.4"},"reference-count":30,"publisher":"SAGE Publications","issue":"1","license":[{"start":{"date-parts":[[2022,10,20]],"date-time":"2022-10-20T00:00:00Z","timestamp":1666224000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2022,10,20]],"date-time":"2022-10-20T00:00:00Z","timestamp":1666224000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Nucleic Acid Therapeutics"],"published-print":{"date-parts":[[2023,2,1]]},"abstract":"<jats:p>\n                    Downregulation of genes involved in the secondary pathology of Duchenne muscular dystrophy, for example, inflammation, fibrosis, and adiposis, is an interesting approach to ameliorate degeneration of muscle and replacement by fibrotic and adiposis tissue. Small interfering RNAs (siRNAs) are able to downregulate target genes, however, delivery of siRNAs to skeletal muscle still remains a challenge. We investigated delivery of fully chemically modified, cholesterol-conjugated siRNAs targeting\n                    <jats:italic toggle=\"yes\">Alk4<\/jats:italic>\n                    , a nontherapeutic target that is expressed highly in muscle. We observed that a single intravenous or intraperitoneal (IP) injection of 10\u2009mg\/kg resulted in significant downregulation of\n                    <jats:italic toggle=\"yes\">Alk4<\/jats:italic>\n                    mRNA expression in skeletal muscles in both wild-type and\n                    <jats:italic toggle=\"yes\">mdx<\/jats:italic>\n                    mice. Treatment with multiple IP injections of 10\u2009mg\/kg led to an overall reduction of\n                    <jats:italic toggle=\"yes\">Alk4<\/jats:italic>\n                    expression, reaching significance in tibialis anterior (39.7%\u2009\u00b1\u20096.2%), diaphragm (32.7%\u2009\u00b1\u20095.8%), and liver (41.3%\u2009\u00b1\u200929.9%) in\n                    <jats:italic toggle=\"yes\">mdx<\/jats:italic>\n                    mice. Doubling of the siRNA dose did not further increase mRNA silencing in muscles of\n                    <jats:italic toggle=\"yes\">mdx<\/jats:italic>\n                    mice. The chemically modified conjugated siRNAs used in this study are very promising for delivery to both nondystrophic and dystrophic muscles and could have major implications for treatment of muscular dystrophy pathology.\n                  <\/jats:p>","DOI":"10.1089\/nat.2022.0021","type":"journal-article","created":{"date-parts":[[2022,10,21]],"date-time":"2022-10-21T11:12:50Z","timestamp":1666350770000},"page":"26-34","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":14,"title":["Efficient Downregulation of\n                    <i>Alk4<\/i>\n                    in Skeletal Muscle After Systemic Treatment with Conjugated siRNAs in a Mouse Model for Duchenne Muscular Dystrophy"],"prefix":"10.1177","volume":"33","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5358-8691","authenticated-orcid":false,"given":"Sarah","family":"Engelbeen","sequence":"first","affiliation":[{"name":"Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Svetlana","family":"Pasteuning-Vuhman","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joke","family":"Boertje-Van der Meulen","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rubina","family":"Parmar","sequence":"additional","affiliation":[{"name":"Alnalym Pharmaceuticals, Cambridge, Massachusetts, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Klaus","family":"Charisse","sequence":"additional","affiliation":[{"name":"Alnalym Pharmaceuticals, Cambridge, Massachusetts, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura","family":"Sepp-Lorenzino","sequence":"additional","affiliation":[{"name":"Alnalym Pharmaceuticals, Cambridge, Massachusetts, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Muthiah","family":"Manoharan","sequence":"additional","affiliation":[{"name":"Alnalym Pharmaceuticals, Cambridge, Massachusetts, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1565-654X","authenticated-orcid":false,"given":"Annemieke","family":"Aartsma-Rus","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maaike","family":"van Putten","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Leiden University Medical Center, Leiden, the 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