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The Splice Index as a prognostic biomarker of strength and function in myotonic dystrophy type 1
Marina Provenzano, … , Melissa A. Hale, on behalf of the Myotonic Dystrophy Clinical Research Network (DMCRN)
Marina Provenzano, … , Melissa A. Hale, on behalf of the Myotonic Dystrophy Clinical Research Network (DMCRN)
Published January 21, 2025
Citation Information: J Clin Invest. 2025;135(4):e185426. https://doi.org/10.1172/JCI185426.
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Clinical Research and Public Health Muscle biology Article has an altmetric score of 14

The Splice Index as a prognostic biomarker of strength and function in myotonic dystrophy type 1

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Abstract

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 (ADF) strength and 10-meter run/fast walk (Pearson’s r = –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 (SIMild, SIModerate, and 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 ClinicalTrials.gov NCT03981575.FUNDING FDA (7R01FD006071), Myotonic Dystrophy Foundation, Wyck Foundation, Muscular Dystrophy Association, Novartis, Dyne, Avidity, PepGen, Takeda, Sanofi Genzyme, Pfizer, Arthex, and Vertex Pharmaceuticals.

Authors

Marina Provenzano, Kobe Ikegami, Kameron Bates, Alison Gaynor, Julia M. Hartman, Aileen Jones, Amanda Butler, Kiera N. Berggren, Jeanne Dekdebrun, Man Hung, Dana M. Lapato, Michael Kiefer, Charles A. Thornton, Nicholas E. Johnson, Melissa A. Hale, on behalf of the Myotonic Dystrophy Clinical Research Network (DMCRN)

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Figure 2

RNA splicing events included in composite Splice Index capture RNA mis-splicing patterns observed across the range of estimated, functional MBNL concentrations in DM1 cohort.

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RNA splicing events included in composite Splice Index capture RNA mis-s...
(A–C) Twenty-two RNA splicing events included in the Splice Index (SI) panel demonstrate variable sensitivity to [MBNL] observed across the spectrum of DM1 participants. Dose-response curves of 22 events included in the composite SI. Ψ values derived from total RNA-seq (Supplemental Table 3) were plotted against estimated functional concentrations of MBNL ([MBNL]inferred). Ψ values from both unaffected adult controls (AdCo, n = 22) and DM1 participants (n = 95) were fit to a 4-parameter dose-response curve and events classified as (A) early, (B) intermediate, and (C) late responder events based on estimated EC50 relative to the observed median of all events. Intermediate responder events were classified based on EC50 values within the interquartile range of 22-event distribution. Early responder were classified based on an estimated EC50 in the 25th percentile, while late responder events had values in the 75th percentile. Curve fit is annotated as the thick solid line and the 95% CI of the fit is shown as the above and below lines. All curve-fit parameters are reported in Supplemental Table 4.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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