BACKGROUND: 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. METHODS: 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 = 52) or a 3-month (n = 37) follow-up visit along with clinical measures of muscle performance. RESULTS: The SI demonstrated significant associations with measures of muscle strength and ambulation, including ankle dorsiflexion strength (ADF) and 10-meter run/fast walk (Pearson r = -0.719 and -0.680, respectively). The SI was relatively stable over 3-months (ICC = 0.863). Latent-class analysis identified three DM1 subgroups stratified by baseline SI (SIMild, SIModerate, SISevere)
SIModerate 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 R² = 0.830). CONCLUSION: 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. TRIAL REGISTRATION: NCT03981575Funding: FDA (7R01FD006071), Myotonic Dystrophy Foundation, Wyck Foundation, Muscular Dystrophy Association, Novartis, Dyne, Avidity, PepGen, Takeda, Sanofi Genzyme, Pfizer, Arthex, and Vertex Pharmaceuticals.