Therapeutics development in myotonic dystrophy type 1

Abstract

Myotonic dystrophy (DM1), the most common adult muscular dystrophy, is a multisystem, autosomal dominant genetic disorder caused by an expanded CTG repeat that leads to nuclear retention of a mutant RNA and subsequent RNA toxicity. Significant insights into the molecular mechanisms of RNA toxicity have led to the previously unforeseen possibility that treating DM1 is a viable prospect. In this review, we briefly present the clinical picture in DM1, and describe how the research in understanding the pathogenesis of RNA toxicity in DM1 has led to targeted approaches to therapeutic development at various steps in the pathogenesis of the disease. We discuss the promise and current limitations of each with an emphasis on RNA-based therapeutics and small molecules. We conclude with a discussion of the unmet need for clinical tools and outcome measures that are essential prerequisites to proceed in evaluating these potential therapies in clinical trials.

Figure 1. Steps in pathogenesis and potential therapeutic targets in DM1

Myotonic Dystrophy results from the expansion of CUG repeats in the mutant RNA, rather than from reduced or dysfunctional protein levels. These repeats form a hairpin structure that can bind and sequester MBNL1 and potentially other RNA-binding proteins. Through mechanisms that are still poorly understood, this toxic RNA also causes hyperphosphorylation and stabilization of CUGBP1. The functional loss of MBNL1 and increase in available CUGBP1 are thought to result in misplicing of downstream RNA targets (largely to fetal isoforms) causing many, if not all, of the observed phenotypes. Attempts have been made to target each of the steps in pathogenesis, although the current effective therapy is limited solely to symptom management.

Figure 2. Conceptual Approach to Therapeutic Design

DM1 is caused by a repeat expansion in the DNA which is then incorporated into a mutant RNA. This toxic RNA then leads to a cascade of mispliced RNA transcripts and multisystem manifestations of disease. The mechanism of pathogenesis is simplest at the stage of the expanded DNA repeat and becomes increasingly more complicated as more cellular processes and pathways are involved in the downstream effects. Thus, intervention at the level of the DNA provides the most therapeutic benefit but is least technically feasible. Conversely, intervention at the level of one mis-spliced target may be most technically approachable, but therapeutic impact is then limited to only one portion of the disease phenotype.