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. 2020 Dec 25;29(2):540–554. doi: 10.1016/j.ymthe.2020.12.022

Figure 7.

Figure 7

Mechanism of Action of QR-421a, a New Application of Steric-Blocking ASOs

The figure depicts a portion of USH2A pre-mRNA containing exons 12, 13, and 14 (middle) in which exon 13 carries missense (blue sign) or premature termination codon (PTC)-introducing (nonsense or frameshift, red sign) retinitis pigmentosa (RP) mutations. Exon 13 encodes half of laminin epidermal growth factor (EGF)-like domain 4, domains 5, 6, 7, and half of laminin EGF-like domain 8 (light blue rectangles highlighted in red). Normally, missense or PTC-introducing RP mutations lead to non-functional full-length or non-functional truncated usherin, respectively (top). QR-421a (+ASO) promotes skipping of exon 13 (depicted by lines connecting exons 12 and 14), leading to the generation of an usherin protein that lacks half of laminin EGF-like domain 4, as well as domains 5, 6, 7, and half of laminin EGF-like domain 8 (bottom), but maintains proper function. Green rectangle, signal peptide; purple rectangle, laminin G-like domain; orange rectangle, laminin N-terminal domain; light blue rectangles, laminin EGF-like domains; green rectangles, fibronectin type III repeats; yellow circles, laminin G; red rectangle, transmembrane domain; blue circle, PDZ binding motif.