fig12

Figure 12. Different ASO- and siRNA-based strategies against Myotonic Dystrophy Type 1. A: MBNL proteins are sequestered by nuclear foci formed by the mRNA from the poly CTG DMPK variant. B: Poly ACG ASO or siRNA lead to DMPK mRNA cleavage and nuclear foci degradation. Alternatively, they can also function as a steric blocker of MBNL binding to the foci, thus releasing the necessary amount of MBNL to restore the adult phenotype splicing pattern. C, D: Since the miRNA (miR)-23b has been shown to repress MBNL expression, the administration of antagomir-23b antagonizes the miRNA (miR)23b which increases MBNL expression, thus compensating for the sequestration of MBNL by variant DMPK mRNA. E: The lack of free MBNL induces mis-splicing toward the fetal phenotype of various proteins. F: Splice correctors ASOs can restore the adult form of the mis-spliced proteins.