Fig. 6: DYNE-101 reduces mutant human DMPK RNA expression in the nucleus and corrects splicing in muscle of a DM1 mouse model. | Communications Medicine

Fig. 6: DYNE-101 reduces mutant human DMPK RNA expression in the nucleus and corrects splicing in muscle of a DM1 mouse model.

From: FORCE platform overcomes barriers of oligonucleotide delivery to muscle and corrects myotonic dystrophy features in preclinical models

Fig. 6

a TfR1;DMSXL mice enable assessment of DYNE-101 ability to target mutant human DMPK RNA via TfR1-mediated uptake. b DMPK, Malat1, Birc5, and Gapdh expression measured by RT-qPCR in total RNA from nuclear (N) and cytoplasmic (C) fractions from gastrocnemius of TfR1hu/mu;DMSXLWT/Tg mice. Data are means +  SD. Each circle represents independent measurements except for analysis of Birc5 and GAPDH expression, where n = 1. c DMPK expression in fractions from gastrocnemius of TfR1hu/mu;DMSXLWT/Tg mice administered with 10 mg/kg ASO-equivalent of DYNE-101 (blue bars) relative to mice injected with vehicle (black bars). Data are means + SD. Each circle represents independent measurements. d DMPK expression measured by RT-qPCR in total RNA from muscles of TfR1hu/mu;DMSXLTg/Tg female mice administered weekly with 10 mg/kg ASO-equivalent of DYNE-101 (blue bars), 28 days after initial injection, relative to expression in corresponding muscles of mice injected with vehicle (black bars). Data are means + SD; data were analyzed by unpaired t test with Welch’s correction, statistically significant differences from vehicle are indicated with exact P values. Each circle represents an individual mouse. e Representative images of nuclei (blue) and DMPK foci (red) in cardiomyocytes used to calculate foci area. Insets display myofibrils (gray) in greyscale. Total DMPK foci area in heart of TfR1hu/mu;DMSXLTg/Tg mice 28 days after initial injection. Data are means + SD, analyzed by unpaired t test: *P < 0.05. Each circle represents an individual mouse. f Composite splicing index in muscle of TfR1hu/mu mice injected with vehicle (gray circle) or TfR1hu/mu;DMSXLTg/Tg mice injected with vehicle (black circle) or DYNE-101 (blue circle), 28 days after initial injection. Horizontal lines are means ± SD; data were analyzed by one-way ANOVA followed by uncorrected Fisher’s LSD test, statistically significant differences from TfR1hu/mu mice injected vehicle or between TfR1hu/mu;DMSXLTg/Tg mice treated with vehicle and DYNE-101 are indicated with exact P values. Each circle represents an individual mouse.

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