Development of Therapeutic Approaches for Myotonic Dystrophies Type 1 and Type 2

Abstract

Myotonic Dystrophies type 1 (DM1) and type 2 (DM2) are complex multisystem diseases without disease-based therapies. These disorders are caused by the expansions of unstable CTG (DM1) and CCTG (DM2) repeats outside of the coding regions of the disease genes: DMPK in DM1 and CNBP in DM2. Multiple clinical and molecular studies provided a consensus for DM1 pathogenesis, showing that the molecular pathophysiology of DM1 is associated with the toxicity of RNA CUG repeats, which cause multiple disturbances in RNA metabolism in patients' cells. As a result, splicing, translation, RNA stability and transcription of multiple genes are misregulated in DM1 cells. While mutant CCUG repeats are the main cause of DM2, additional factors might play a role in DM2 pathogenesis. This review describes current progress in the translation of mechanistic knowledge in DM1 and DM2 to clinical trials, with a focus on the development of disease-specific therapies for patients with adult forms of DM1 and congenital DM1 (CDM1).

Keywords: clinical trials; congenital myotonic dystrophy; myotonic dystrophy; myotonic dystrophy type 2.

Figure 1

(A). Clinical forms of DM1 are shown. The longest CTG expansions are in CDM1 patients. Patients with short CTG repeats are affected later in life with mild symptoms. (B). DM2 is an adult disease with vary variable length of CCTG expansions.

Figure 2

(A–E): The main therapeutic approaches for DM1 are shown. See text for details. DMPK gene and DMPK mRNA are shown as red and dark grey boxes. MBNL1 protein is shown in pink. Inactive CUGBP1 is shown in brown, while active CUGBP1 (CUGBP1^Act) is shown in blue. Other RNA-binding proteins might participate in the regulation of MBNL1 and CUGBP1 targets in DM1.

Figure 3

Possible involvement of GSK3β kinase in the regulation of AMPK in DM1. In normal cells, high levels of active AMPK are maintained by the low levels of GSK3β activity. However, in DM1 cells, GSK3β is elevated. Since AMPK is a substrate of GSK3β, the increase in GSK3β may lead to a reduction in AMPK in DM1 cells. It is expected that the correction of GSK3β activity with tideglusib (TG) in DM1 cells might normalize levels of AMPK.

Figure 4

(A–C): The models of the proposed therapeutic approaches for DM2 (see text). Mutant CNBP gene and CNBP mRNA are shown as blue and brown boxes.