Background
Facioscapulohumeral muscular dystrophy (FSHD) is characterized by progressive, often asymmetric, skeletal muscle degeneration driven primarily by aberrant expression of the DUX4 transcription factor. The underlying genetics are complex, with DUX4 expression being mosaic, sporadic, and stochastic. While many current therapeutic strategies focus largely on suppressing DUX4, or its downstream pathology, there remains a critical need for complementary approaches that enhance the muscle’s intrinsic capacity for repair. Recent work has highlighted Adaptor-Associated Kinase 1 (AAK1) as an important regulator of the muscle regeneration process in both healthy and dystrophic muscle, whereby inhibition of AAK1 results in enhanced regeneration and repair, leading to significant improvements in muscle force. Based on these findings, we hypothesized that SAT-3247 could address aspects of FSHD muscle pathology independent of direct DUX4 suppression. To test this, we evaluated SAT-3247 in the FLExDUX4.CRE mouse model of FSHD to determine whether augmenting regenerative signaling through AAK1 modulation can improve muscle function in the context of DUX4-mediated damage.
Methods
Male and female FLExDUX4.CRE mice were assigned to one of five groups based on body weight and sex: Group 1 – Vehicle; Group 2 – 3mg/kg, Group 3 – 10mg/kg, Group 4 – 30mg/kg, and Group 5 – 0.01mg/kg SAT-3247. Groups 2-4 were dosed over four consecutive days, followed by 3 days off per week. Group 5 was administered daily dosing. FLExDUX4.CRE mice were not induced with tamoxifen. Mice were treated with either vehicle or SAT-3247 by oral gavage (PO). After 4 weeks (Day 29), 8 weeks (Day 57) and 12 weeks (Day 85) of treatment, in vivo muscle function was measured.
Results
Male and female FLExDUX4.CRE mice treated with SAT-3247 displayed significant force improvements at 4, 8, and 12 weeks post dosing initiation. Force improvements increased over weeks 4 to 8, and again over weeks 8 to 12. After 12 weeks of dosing, 10mg/kg SAT-3247 appeared to result in the largest improvement in force.
Conclusion
Collectively, these results suggest that SAT-3247 significantly improves muscle function in both male and female FLExDUX4.CRE mice, modeling FSHD, supporting its potential utility in people living with FSHD.