677P The Splice Index as a prognostic biomarker of strength and function in myotonic dystrophy type 1.

Myotonic dystrophy type 1 (DM1) is caused by a CTG repeat expansion in DMPK that leads to global dysregulation of RNA splicing and subsequent multisystemic symptomatic presentation. The gradual decline in physical function of DM1 individuals necessitates large participant numbers or extended trial durations when using motor function tests to demonstrate significant benefit of disease-modifying interventions. In this setting a biomarker capable of measuring the association between RNA mis-splicing and muscle weakness with prognostic utility would be useful for evaluating early indications of functional response or selection of appropriate participants at trial enrollment. We evaluated a 22-event composite measure of RNA mis-splicing called the Splice Index (SI) as a potential biomarker of muscle weakness in DM1. A total of 46 adults with DM1 provided baseline tibialis anterior muscle biopsies along with measurements of muscle strength, functional mobility, and myotonia, the hallmark symptom of DM1. A subset of 34 participants provided 3-month biopsies and measurements to assess longitudinal stability of the SI. The SI was derived using muscle RNA and a streamlined, easy to deploy, amplicon sequencing methodology to derive percent exon inclusion (PSI) values with high resolution. Individuals were then scored on a linear scale based on the average of a normalized PSI for all 22 splicing events. The SI demonstrated significant associations with ankle dorsiflexion (ADF) (Pearson r = -0.697) and other indicators of muscle function, including 10-meter run/fast walk and hand grip strength. These correlations were primarily driven by strong individual associations of CACNA1S and CLCN1 with all outcome measures. Mis-splicing of these two events is linked to both myotonia and muscle weakness in DM1 models. In a timepoint mismatch analysis we observed a significantly stronger correlation of baseline SI to 3-month ADF (r = -0.78) indicating that RNA mis-splicing as captured by the SI may be predictive of future performance. Linear regression modeling revealed that the combination of baseline ADF and SI was highly predictive of strength at 3 months in our cohort (adjusted R2 = 0.83). Importantly, while the SI exhibited reliability in cross-sectional comparisons between baseline and 3-months, asymmetric variation in SI dynamics within mild and moderately affected participant subgroups may affect this reliability. Overall, the SI is a reliable biomarker that accurately captures associations with physical strength and functional mobility in DM1 adults. Early analyses also suggest its potential value to predict future function. The SI can sensitively detect changes in mis-splicing over 3-months, which may be more dynamic than expected given the slow clinical progression of DM1. Collectively, our validation underscores this biomarker's utility for assessment of disease severity/progression and potential stratification of individuals for trial enrollment. [ABSTRACT FROM AUTHOR]