{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T21:40:26Z","timestamp":1791322826790,"version":"4.3.1"},"reference-count":49,"publisher":"American Society for Clinical Investigation","issue":"4","license":[{"start":{"date-parts":[[2025,2,17]],"date-time":"2025-02-17T00:00:00Z","timestamp":1739750400000},"content-version":"vor","delay-in-days":41,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000038","name":"U.S. Food and Drug Administration","doi-asserted-by":"crossref","award":["7R01FD006071"],"award-info":[{"award-number":["7R01FD006071"]}],"id":[{"id":"10.13039\/100000038","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100003975","name":"Myotonic Dystrophy Foundation","doi-asserted-by":"crossref","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/100003975","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Wyck Foundation","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"DOI":"10.13039\/100005202","name":"Muscular Dystrophy Association","doi-asserted-by":"crossref","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/100005202","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Novartis","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"name":"Dyne","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"name":"Avidity","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"name":"PepGen","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"name":"Takeda","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"DOI":"10.13039\/100013995","name":"Sanofi Genzyme","doi-asserted-by":"crossref","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/100013995","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100004319","name":"Pfizer","doi-asserted-by":"crossref","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/100004319","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Arthex","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"DOI":"10.13039\/100011022","name":"Vertex Pharmaceuticals","doi-asserted-by":"crossref","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/100011022","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,2,17]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND<\/jats:title>\n                    <jats:p>Myotonic dystrophy type 1 (DM1) is a multisystemic, CTG repeat expansion disorder characterized by a slow, progressive decline in skeletal muscle function. A biomarker correlating RNA mis-splicing, the core pathogenic disease mechanism, and muscle performance is crucial for assessing response to disease-modifying interventions. We evaluated the Myotonic Dystrophy Splice Index (SI), a composite RNA splicing biomarker incorporating 22 disease-specific events, as a potential biomarker of DM1 muscle weakness.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>\n                      Total RNA sequencing of tibialis anterior biopsies from 58 DM1 participants and 33 unaffected\/disease controls was used to evaluate RNA splicing events across the disease spectrum. Targeted RNA sequencing was used to derive the SI from biopsies collected at baseline (\n                      <jats:italic>n<\/jats:italic>\n                      = 52) or a 3-month (\n                      <jats:italic>n<\/jats:italic>\n                      = 37) follow-up visit along with clinical measures of muscle performance.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>\n                      The SI demonstrated significant associations with measures of muscle strength and ambulation, including ankle dorsiflexion (ADF) strength and 10-meter run\/fast walk (Pearson\u2019s\n                      <jats:italic>r<\/jats:italic>\n                      = \u20130.719 and \u20130.680, respectively). The SI was relatively stable over 3 months (intraclass correlation coefficient [ICC] = 0.863). Latent-class analysis identified 3 DM1 subgroups stratified by baseline SI (SI\n                      <jats:sub>Mild<\/jats:sub>\n                      , SI\n                      <jats:sub>Moderate<\/jats:sub>\n                      , and SI\n                      <jats:sub>Severe<\/jats:sub>\n                      ); SI\n                      <jats:sub>Moderate<\/jats:sub>\n                      individuals had a significant increase in the SI over 3 months. Multiple linear regression modeling revealed that baseline ADF and SI were predictive of strength at 3 months (adjusted\n                      <jats:italic>R<\/jats:italic>\n                      \u00b2 = 0.830).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSION<\/jats:title>\n                    <jats:p>The SI is a reliable biomarker that captures associations of RNA mis-splicing with physical strength and mobility and has prognostic utility to predict future function, establishing it as a potential biomarker for assessment of therapeutic target engagement.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>TRIAL REGISTRATION<\/jats:title>\n                    <jats:p>ClinicalTrials.gov NCT03981575.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>FUNDING<\/jats:title>\n                    <jats:p>FDA (7R01FD006071), Myotonic Dystrophy Foundation, Wyck Foundation, Muscular Dystrophy Association, Novartis, Dyne, Avidity, PepGen, Takeda, Sanofi Genzyme, Pfizer, Arthex, and Vertex Pharmaceuticals.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1172\/jci185426","type":"journal-article","created":{"date-parts":[[2025,1,21]],"date-time":"2025-01-21T11:43:01Z","timestamp":1737459781000},"source":"Crossref","is-referenced-by-count":28,"title":["The Splice Index as a prognostic biomarker of strength and function in myotonic dystrophy type 1"],"prefix":"10.1172","volume":"135","author":[{"given":"Marina","family":"Provenzano","sequence":"first","affiliation":[{"name":"Center for Inherited Myology Research and"},{"name":"Department of Neurology, School of Medicine, Virginia Commonwealth University, Richmond, Virginia, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kobe","family":"Ikegami","sequence":"additional","affiliation":[{"name":"Center for 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