{"doi":"10.1172/jci185426","title":"The Splice Index as a prognostic biomarker of strength and function in myotonic dystrophy type 1","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’s\n                      <jats:italic>r</jats:italic>\n                      = –0.719 and –0.680, 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                      ² = 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>","journal":"Journal of Clinical Investigation","year":2025,"id":654718,"datarank":0.47032413238937254,"base_score":3.1354942159291497,"endowment":3.1354942159291497,"self_citation_contribution":0.47032413238937254,"citation_network_contribution":0.0,"self_endowment_contribution":0.47032413238937254,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":22,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1486419,"name":"Kobe Ikegami","orcid":"0009-0000-9159-063X","position":1,"is_corresponding":false},{"id":738038,"name":"Kameron Bates","orcid":null,"position":2,"is_corresponding":false},{"id":1708776,"name":"Alison Gaynor","orcid":null,"position":3,"is_corresponding":false},{"id":1708777,"name":"Julia M. Hartman","orcid":null,"position":4,"is_corresponding":false},{"id":1400279,"name":"Aileen Jones","orcid":"0009-0003-2882-3025","position":5,"is_corresponding":false},{"id":1400280,"name":"Amanda Butler","orcid":"0009-0009-1809-3341","position":6,"is_corresponding":false},{"id":1247333,"name":"Kiera N. Berggren","orcid":"0000-0001-6198-8153","position":7,"is_corresponding":false},{"id":1708778,"name":"Jeanne Dekdebrun","orcid":null,"position":8,"is_corresponding":false},{"id":692349,"name":"Man Hung","orcid":"0000-0003-2827-3740","position":9,"is_corresponding":false},{"id":354203,"name":"Dana M. Lapato","orcid":"0000-0001-8169-9754","position":10,"is_corresponding":false},{"id":666068,"name":"Michael Kiefer","orcid":"0000-0003-0891-2592","position":11,"is_corresponding":false},{"id":333360,"name":"Charles A. Thornton","orcid":"0000-0002-2124-6080","position":12,"is_corresponding":false},{"id":288178,"name":"Nicholas E. Johnson","orcid":"0000-0002-3917-4257","position":13,"is_corresponding":false},{"id":384350,"name":"Melissa A. Hale","orcid":null,"position":14,"is_corresponding":false},{"id":879854,"name":"Marina Provenzano","orcid":"0009-0008-9781-1905","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"The Splice Index as a prognostic biomarker of strength and function in myotonic dystrophy type 1","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’s\n                      <jats:italic>r</jats:italic>\n                      = –0.719 and –0.680, 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                      ² = 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>","is_dataset_classified":null,"base_score":3.091042453358316,"endowment":3.091042453358316,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"39836447","pmcid":"PMC11827844","openalex_id":"https://openalex.org/W4406665761","authors":[],"funders":[{"funder_name":"U.S. Food and Drug Administration","grant_id":"7R01FD006071","title":null},{"funder_name":"Myotonic Dystrophy Foundation","grant_id":"N/A","title":null},{"funder_name":"FDA HHS","grant_id":"R01 FD006071","title":null}],"total_grants":3,"fwci":9.7896,"citation_percentile":0.98743188,"influential_citations":0,"citation_trend":[{"year":2025,"count":12},{"year":2026,"count":9}],"oa_status":"gold","license":"cc-by","oa_locations":[{"url":"http://www.jci.org/articles/view/185426/files/pdf","host_type":"journal"},{"url":"http://www.jci.org/articles/view/185426/files/pdf","host_type":"publisher"},{"url":"https://www.jci.org/articles/view/185426/files/pdf","host_type":"publisher"},{"url":"https://doi.org/10.1172/jci185426","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/39836447","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/11827844","host_type":"repository"},{"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC11827844/pdf/jci-135-185426.pdf","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC11827844","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC11827844?pdf=render","host_type":"Europe_PMC"}],"fields_of_study":["Genetic Neurodegenerative Diseases","Mitochondrial Function and Pathology","Adult","Female","Humans","Male","Middle Aged","Biomarkers","Muscle Strength","Muscle, Skeletal","Myotonic Dystrophy","Prognosis","RNA Splicing"],"mesh_terms":["Adult","Female","Humans","Male","Middle Aged","Myotonic Dystrophy","Prognosis","RNA Splicing","Biomarkers","Muscle, Skeletal","Muscle Strength"],"keywords":["Myotonic dystrophy","Biomarker","Index (typography)","Medicine","splice","Function (biology)","Genetics","Computational biology","Internal medicine","Biology","Oncology","Bioinformatics","Computer science","Gene","World Wide Web","RNA processing","Skeletal muscle","Neuromuscular disease","Muscle Biology"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Zero hunger"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[{"name":"bioproject"},{"name":"nct"},{"name":"doi"}],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-11T08:02:19.406072Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}