The Splice Index as a prognostic biomarker of strength and function in myotonic dystrophy type 1
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)
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)
View: Text | PDF
Clinical Research and Public Health Muscle biology

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

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)

×

Figure 1

DM1 participant cohort displays broad spectrum of RNA splicing dysregulation, as assessed by total RNA-seq.

Options: View larger image (or click on image) Download as PowerPoint
DM1 participant cohort displays broad spectrum of RNA splicing dysregula...
(A) DM1 participant demographic information, including sample size, age at biopsy, and sex distribution in complete cross-sectional and longitudinal cohort subset. The mean normalized performance on clinical outcome measures for the cross-sectional DM1 cohort are reported along with sample size, mean ± SD, and 95% CI. Additional demographic information of all samples used in this report are provided in Supplemental Table 1. (B) Box-and-whisker plots of outcome measure performance in DM1 cross-sectional cohort, where the lines represents median performance, the bounds of the boxes are the 25th and 75th percentiles, and whiskers extend to maximum and minimum values. (C) Heatmap displaying estimated percentage spliced (Ψ) of top 50 significantly dysregulated skipped exon (SE) events between DM1 versus unaffected adult controls (AdCo) and disease control reference groups (DMD and LGMD) subjected to total RNA-seq (|ΔΨ| ≥ 0.1, FDR ≤ 0.05). Both rows (SE events) and columns (individual samples) were subjected to hierarchical clustering. Sample group and sex are annotated above the heatmap and individual IDs are reported below. (D) Ψ values for specific SE events in all sample groups (n = 22 AdCo, n = 95 DM1, n = 10 LGMD, and n = 1 DMD). Bar represents median. **P < 0.01; ****P < 0.0001. NS, not significant. One-way ANOVA with Tukey’s correction, where DMD was not included in the analysis due to insufficient sample size.