Changes in RNA splicing as a surrogate endpoint for myotonic dystrophy Type 1 (DM1) clinical trials.

Myotonic dystrophy type 1 (DM1) is a slowly progressive, multi-systemic disorder with clinical phenotypes that vary by age of onset and severity of symptoms. It is the most common form of muscular dystrophy occurring in adults. Abnormal regulation of alternative splicing of pre-mRNA results from a repeat expansion mutation in the dystrophia myotonica protein kinase () gene. The resulting spliceopathy is universal across affected individuals and clinical phenotypes and drives the clinical manifestations of DM1, which include a diverse array of signs and symptoms affecting most organ systems. There is currently no disease-modifying treatment for DM1. Heterogeneity in the developmental and degenerative features and patterns of DM1 complicates the stratification, powering, and execution of interventional clinical trials in a reasonable timeframe. The use of splicing change as a surrogate endpoint in DM1 evolved from the principle that the degree of DM1-affected exons relates to the level of functional muscleblind-like (MBNL) RNA-binding protein activity in muscle cell nuclei. Surrogate endpoints based on panels of mis-splicing events reflecting the underlying DM1 molecular mechanism are reasonably likely to predict clinical benefit in a timely fashion, thus enabling accelerated clinical development of therapies that address unmet needs in DM1. Natural history data from the DM1 population support a strong correlation between dysregulated splicing and muscle function and point to the utility of a composite splicing index as a surrogate endpoint to predict future functional benefit, particularly in clinical trials of reasonable duration. Ongoing and future clinical trials will hopefully address the validity of surrogate endpoints using changes in splicing and whether the correction of spliceopathy correlates with meaningful clinical outcome assessments in individuals with DM1.