Fig. 4: Branaplam modulates human mHTT transcript and protein levels in the brain and rescues narrow beam performance in BacHD mice.

Q-PCR analysis of HTT Exon 50a inclusion in a, striatum b, cortex c, thalamus and d, cerebellum in response to vehicle or branaplam administrated at 6, 12, and 24 mg/kg every other day for a total of three doses. Data are the mean ± SEM of four mice per group, ****P < 0.0001, ***P < 0.001, **P < 0.01, *P < 0.05 vehicle vs branaplam-treated groups, one-way ANOVA followed by Bonferroni’s post hoc. e mHTT protein levels in the striatum of BacHD mice (n = 6) treated with 12 mg/kg or 24 mg/kg of branaplam for 3 weeks and analyzed at the indicated timepoints after last treatment. Data are the mean ± SEM of six mice per group. One-way ANOVA with Dunnett’s multiple comparisons test: **P = 0.048, ***P = 0.0003, ****P < 0.0001, and (b) ****P < 0.0001, **P value = 0.003. f mHTT protein levels in the cortex of BacHD mice (n = 6) treated with 12 mg/kg or 24 mg/kg of branaplam and taken down at indicated timepoints. Data are the mean ± SEM of six mice per group. One-way ANOVA with Dunnett’s multiple comparisons test: ***P value = 0.0008, (Vehicle vs 24 mg/kg, 72 h) ****P value <0.0001. g Time-course of mHTT protein levels in the striatum of BacHD mice (n = 6) treated with 12 mg/kg or 24 mg/kg of branaplam for 3 weeks and analyzed at the indicated timepoints after last treatment. Data are the mean ± SEM of six mice per group. One-way ANOVA with Dunnett’s multiple comparisons test: **P value = 0.0017, ****P value <0.0001. h Branaplam treatment in BACHD females rescues the number of slips on the narrow beam. Data represent mean ± SEM of 12 WT and 15 BACHD mice treated with vehicle, and 14 HD mice treated with branaplam. *P ≤0.05 and **P ≤0.01 indicates a significant difference detected by a Kruskal–Wallis test with Dunn’s multiple comparisons tests. i HTT transcripts in whole-blood samples from Type I SMA patients dosed weekly with branaplam. The mean age at screening was 4.21 months (SD, 1.481 months; range, 1.8‒7.5 months) with slightly more females (57.9%) enrolled into the study. The gray curve depicts average number of copies of HTT mRNA transcripts with exon 50a inclusion per 1000 GUSB mRNA copies in the blood of infants with SMA Type I after multiple weekly administrations branaplam. The red curve represents the average percentage change from baseline in total blood HTT mRNA levels in infants with SMA type I after multiple weekly administration of oral branaplam as measured using primers upstream (exons 36–37) of exon 50a. Error Bars represent mean ± SEM.