Figure 5. Combination treatment rescues more mis-splicing events than either drug alone and does not globally disrupt gene expression in the HSA^LR DM1 mouse model.

Global analysis of ES events that showed a greater than 10% change in PSI between WT and HSA^LR mice were evaluated for mis-splicing rescue (p<0.01, FDR<0.1) with (A) 600 mg kg⁻¹ erythromycin, (B) 10 mg kg⁻¹ pafuramidine (PaF), (C) the combination (EM+PaF), and (D) 15 mg kg⁻¹ pafuramidine (PaF) per oral administration daily for 14 days. The number of ES events that showed mis-splicing Rescue (black bar) of > 10%, Over-rescue (golden rod bar) of > 110% or Mis-rescue (grey bar) of < −10% for each treatment are displayed. The average percent rescue for all ‘Rescued’ ES events for a given treatment is displayed above the black bar. Global differential gene expression analysis determined via RNA-seq for (E) 600 mg kg⁻¹ erythromycin, (F) 10 mg kg⁻¹ pafuramidine (PaF), (G) the combination (EM+PaF) and (H) 15 mg kg⁻¹ pafuramidine (PaF)versus control HSA^LR mice. The number of genes that showed expression Rescue (black bar) of > 10%, Over-rescue (golden rod bar) of > 110% or Mis-rescue (grey bar) of < −10% for each treatment are displayed. Off-target (light grey bar) are genes that showed a greater than 10% change in expression and are not typically differentially expressed between WT and HSA^LR mice (p<0.1). MAplots of differential gene expression analysis determined via RNA-seq for (I) 600 mg kg⁻¹ erythromycin, (J) 10 mg kg⁻¹ pafuramidine (PaF), (K) the combination (EM+PaF) and (L) 15 mg kg⁻¹ pafuramidine (PaF) versus control HSA^LR mice. Red dots represent gene with significantly altered expression (p<0.1). Grey dots represent genes that were not significantly differentially expressed.