Establishing Biomarkers and Clinical Endpoints in Myotonic Dystrophy Type-1

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Abstract Myotonic dystrophy type-1 (DM1) is the most common form of muscular dystrophy in adults. Individuals with myotonic dystrophy develop progressive muscle weakness, early cataracts, cardiac arrhythmias, and other symptoms. The genetic basis is an expansion of CTG repeats in the non-coding region of DMPK, which causes a deleterious gain-of-function by DMPK mRNA. RNA binding proteins become trapped on repetitive RNA, causing loss of splicing regulatory functions. The discovery that DM1 is instigated by RNA toxicity and misregulated splicing has led to therapeutic targets and candidate biomarkers. Several therapeutic approaches are under development, including 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 are proposing to overcome these limitations by expanding the scope of natural history data (Aim 1) and completing the steps of biomarker qualification (Aim 2). We plan to enroll 500 adults with DM1 at eight sites of the Myotonic Dystrophy Clinical Research Network. Study assessments will be repeated after 1 and 2 years. Our proposed entry criteria are non- restrictive to capture data across the broad spectrum of DM1 severity. Based on preliminary data from our current multicenter study of 113 patients, we selected a concise set of clinical measures showing acceptable reliability and responsivity to progression. The proposed study is designed to establish minimal clinically important differences, identify baseline characteristics to predict future progression, and provide a basis for stratification, or sample size selection 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. Our goal is to optimize methods for sample collection and processing, extend our reference dataset of splicing measurements, and formally establish that splicing data are archival, so that biomarker data are comparable across laboratories and to reference data. 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.