{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T16:08:28Z","timestamp":1790957308353,"version":"4.1.0"},"reference-count":42,"publisher":"Oxford University Press (OUP)","issue":"20","license":[{"start":{"date-parts":[[2022,8,10]],"date-time":"2022-08-10T00:00:00Z","timestamp":1660089600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Dyne Therapeutics, Inc"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,11,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Current therapies for Duchenne muscular dystrophy (DMD) use phosphorodiamidate morpholino oligomers (PMO) to induce exon skipping in the dystrophin pre-mRNA, enabling the translation of a shortened but functional dystrophin protein. This strategy has been hampered by insufficient delivery of PMO to cardiac and skeletal muscle. To overcome these limitations, we developed the FORCETM platform consisting of an antigen-binding fragment, which binds the transferrin receptor 1, conjugated to an oligonucleotide. We demonstrate that a single dose of the mouse-specific FORCE\u2013M23D conjugate enhances muscle delivery of exon skipping PMO (M23D) in mdx mice, achieving dose-dependent and robust exon skipping and durable dystrophin restoration. FORCE\u2013M23D-induced dystrophin expression reached peaks of 51%, 72%, 62%, 90%\u00a0and 77%, of wild-type levels in quadriceps, tibialis anterior, gastrocnemius, diaphragm, and heart, respectively, with a single 30 mg\/kg PMO-equivalent dose. The shortened dystrophin localized to the sarcolemma, indicating expression of a functional protein. Conversely, a single 30 mg\/kg dose of unconjugated M23D displayed poor muscle delivery resulting in marginal levels of exon skipping and dystrophin expression. Importantly, FORCE\u2013M23D treatment resulted in improved functional outcomes compared with administration of unconjugated M23D. Our results suggest that FORCE conjugates are a potentially effective approach for the treatment of DMD.<\/jats:p>","DOI":"10.1093\/nar\/gkac641","type":"journal-article","created":{"date-parts":[[2022,8,9]],"date-time":"2022-08-09T20:10:46Z","timestamp":1660075846000},"page":"11401-11414","source":"Crossref","is-referenced-by-count":70,"title":["Enhanced exon skipping and prolonged dystrophin restoration achieved by TfR1-targeted delivery of antisense oligonucleotide using FORCE conjugation in\n                    <i>mdx<\/i>\n                    mice"],"prefix":"10.1093","volume":"50","author":[{"given":"Cody A","family":"Desjardins","sequence":"first","affiliation":[{"name":"Research Department , Dyne Therapeutics Inc., Waltham , MA \u00a002451,\u00a0 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica","family":"Yao","sequence":"additional","affiliation":[{"name":"Research Department , Dyne Therapeutics Inc., Waltham , MA \u00a002451,\u00a0 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Hall","sequence":"additional","affiliation":[{"name":"Research Department , Dyne Therapeutics Inc., Waltham , MA \u00a002451,\u00a0 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma","family":"O\u2019Donnell","sequence":"additional","affiliation":[{"name":"Research Department , Dyne Therapeutics Inc., Waltham , MA \u00a002451,\u00a0 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reshmii","family":"Venkatesan","sequence":"additional","affiliation":[{"name":"Research Department , Dyne Therapeutics Inc., Waltham , MA \u00a002451,\u00a0 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sean","family":"Spring","sequence":"additional","affiliation":[{"name":"Research Department , Dyne Therapeutics Inc., Waltham , MA \u00a002451,\u00a0 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aiyun","family":"Wen","sequence":"additional","affiliation":[{"name":"Research Department , Dyne Therapeutics Inc., Waltham , MA \u00a002451,\u00a0 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nelson","family":"Hsia","sequence":"additional","affiliation":[{"name":"Research Department , Dyne Therapeutics Inc., Waltham , MA \u00a002451,\u00a0 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peiyi","family":"Shen","sequence":"additional","affiliation":[{"name":"Research Department , Dyne Therapeutics Inc., Waltham , MA \u00a002451,\u00a0 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan","family":"Russo","sequence":"additional","affiliation":[{"name":"Research Department , Dyne Therapeutics Inc., Waltham , MA \u00a002451,\u00a0 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Lan","sequence":"additional","affiliation":[{"name":"Research Department , Dyne Therapeutics Inc., Waltham , MA \u00a002451,\u00a0 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tyler","family":"Picariello","sequence":"additional","affiliation":[{"name":"Research Department , Dyne Therapeutics Inc., Waltham , MA \u00a002451,\u00a0 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kim","family":"Tang","sequence":"additional","affiliation":[{"name":"Research Department , Dyne Therapeutics Inc., Waltham , MA \u00a002451,\u00a0 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy","family":"Weeden","sequence":"additional","affiliation":[{"name":"Research Department , Dyne Therapeutics Inc., Waltham , MA \u00a002451,\u00a0 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Zanotti","sequence":"additional","affiliation":[{"name":"Research Department , Dyne Therapeutics Inc., Waltham , MA \u00a002451,\u00a0 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5586-9895","authenticated-orcid":false,"given":"Romesh","family":"Subramanian","sequence":"additional","affiliation":[{"name":"Research Department , Dyne Therapeutics Inc., Waltham , MA \u00a002451,\u00a0 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5347-5825","authenticated-orcid":false,"given":"Oxana","family":"Ibraghimov-Beskrovnaya","sequence":"additional","affiliation":[{"name":"Research Department , Dyne Therapeutics Inc., Waltham , MA \u00a002451,\u00a0 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,8,10]]},"reference":[{"key":"2022120608433677100_B1","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/0960-8966(91)90039-U","article-title":"Population frequencies of inherited neuromuscular diseases\u2013a world survey","volume":"1","author":"Emery","year":"1991","journal-title":"Neuromuscul. 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