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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 5

Splice Index (SI) demonstrates dynamic shifts over 3 months in select DM1 subcohorts stratified by baseline SI score.

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Splice Index (SI) demonstrates dynamic shifts over 3 months in select DM...
(A) SI score significantly increases between baseline (BL) and 3 months (3M) in SIModerate group. DM1 participants in longitudinal cohort were stratified by BL SI score: SIMild (0 ≤ BL SI ≤ 0.4, n = 11), SIModerate (0.4 < BL SI ≤ 0.75, n = 13), and SISevere (0.75 < BL SI ≤ 1.0, n = 11). Data represented as mean ± SD. **P < 0.01 by paired, 2-tailed t test. NS, not significant. Connected scatter plots are also displayed to show shifts in BL and 3M paired SI values for each DM1 individual. (B) Kernel density estimation plot of BL and 3M SI distributions in SIMild, SIModerate, and SISevere groups. (C and D) Kernel density estimation plot of BL and 3M (C) ADF and (D) 10MRW distributions in SIMild, SIModerate, and SISevere groups. ADF is reported as the percentage of predicted strength as compared with unaffected individuals and 10MRW in speed (m/s).

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

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