From diagnosis to therapy in Duchenne muscular dystrophy

Figures

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  Figure 1.. Schematic diagram of the structure of dystrophin, minigenes and utrophin and exon skipping approaches. (A) Full length dystrophin comprises N-terminal actin-binding domain (NTD), four hinge domains (H), 24 spectrin-like repeats (R) that form the rod domain, the cysteine rich domain (CRD) which binds the dystroglycoprotein complex and the C-terminal domain (CTD). (B) Schematic presentation of exon skipping. Patients with DMD have mutations which disrupt the open reading frame of the dystrophin pre-RNA. In this example, exon 50 is deleted, creating an out-of-frame mRNA and leading to the synthesis of a truncated non-functional unstable dystrophin. An antisense oligonucleotide directed against exon 51 can induce effective skipping of exon 51 and restore the open reading frame, thereby generating an internally deleted but partially functional dystrophin.

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  Figure 2.. Target deconvolution studies for the utrophin modulator ezutromid. Input from chemoproteomics, phenotype profiling and RNA seq converged on the aryl hydrocarbon receptor, which was further confirmed with target engagement and target validation studies, (based on figures from [30]).

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  Figure 3.. Regulation of biological processes via AhR and the relationship with utrophin. (a) Crystal structure of truncated AhR (red) and AhR nuclear translocator (ARNT, blue) heterodimer in complex with DNA, PDB deposit: 5v0l. (b) Treatment with AhR ligands results in nuclear translocation, dimerization with ARNT, binding to DNA and transcription of XRE/DRE elements such as AhRR and Cyp1a1/Cyp1b1. (c) Treatment of myoblasts with AhR antagonists like ezutromid down-regulates nuclear translocation of AhR by inhibiting dimerisation with ARNT, and/or DNA binding. This results in down-regulating the transcription of AhR responsive genes, and at the same time increases utrophin and AhR transcription and translation.