Establishing Biomarkers and Clinical Endpoints in Myotonic Dystrophy Type-1 (Renewal)

点击翻译按钮获取中文摘要

Abstract Myotonic dystrophy type-1 (DM1) is the most common form of muscular dystrophy in adults. The genetic basis is an expansion of CTG repeats in the non-coding region of DMPK, the gene encoding DM protein kinase. Individuals with myotonic dystrophy develop progressive muscle weakness, early cataracts, cardiac arrhythmias, and other symptoms. The disease mechanism involves a deleterious gain-of-function by the mutant DMPK mRNA, a process first described in DM1, known as RNA toxicity. RNA binding proteins become trapped on repetitive RNA, causing loss of splicing regulatory functions. Splicing changes contribute to DM1 symptoms and also may serve as biomarkers of disease severity. The discovery that DM1 is instigated by toxicity of one RNA species and characterized by misregulated splicing of other RNAs has furnished good therapeutic targets and candidate biomarkers. Several therapeutic approaches are under development and two are in early phase clinical trials. However, the design and conduct of clinical trials is limited by disease heterogeneity, scarcity of natural history data, and the lack of proven clinical endpoints or biomarkers of drug impact. We have begun a natural history study to define clinical endpoints, biomarkers, and patient characteristics for clinical trials. This study, END-DM1, has enrolled 277 participants but early progress was hampered by the COVID-19 pandemic. The current renewal application seeks to complete the study of clinical outcome assessments (Aim 1) and biomarkers (Aim 2) in DM1. We will complete enrollment of 700 adults with DM1 at 16 sites of the Myotonic Dystrophy Clinical Research Network with return visits at 12 and 24 months. Based on preliminary data, we selected a concise set of clinical measures showing acceptable reliability and responsivity to disease progression. The proposed study is designed to establish minimal clinically important differences for different measures in this population, identify baseline characteristics that predict future progression, and provide a rational basis for stratification, selection of sample size, or enrichment in future trials. Aim 2 will build on our previous efforts to develop RNA splicing biomarkers of DM1 severity and therapeutic response. This Aim is focused on tissue biomarkers that provide direct evidence of target engagement in skeletal muscle. We will assess a panel of DM1-affected splice events using a novel method that involves targeted high-throughput sequencing. Completion of this study is the logical next step to lay the groundwork for effective clinical trials in DM1, and keep pace with the rapidly expanding preclinical efforts to develop an effective drug treatment.