FDA-approved JAK inhibitors (Tofacitinib and Ruxolitinib) failed to improve the phenotype of dystrophin-deficient mdx mice.



Poster Number: 123


Candela Bosco , Kitipong Uaesoontrachoon , Sadish Srinivassane , Joyce Rowsell B.S, Pia Elustondo PhD, Kanneboyina Nagaraju


2. AGADA Biosciences Inc., 3. AGADA Biosciences Inc., 4. AGADA Biosciences Inc., 5. AGADA Biosciences Inc.

Objective: Repurposing of Tofacitinib and Ruxolitinib, FDA-approved Janus Kinase Inhibitors, would be both time and cost effective in finding a potential treatment for DMD. Inflammation, fibrosis, and failed regeneration of muscle are the hallmarks of the dystrophic pathology. JAK inhibitors affect all three processes. Therefore, we hypothesized that inhibition of the JAK/STAT pathway would improve muscle function in the mdx mouse model.
Methods: Male BL10-mdx mice and wildtype controls (age: 12 weeks) were treated daily via oral gavage for 15 weeks across six groups (n=15): BL10 and mdx vehicle; and mdx treated with Tofacitinib at 15 or 30 mg/kg and Ruxolitinib at 45 or 90 mg/kg. We measured weekly bodyweights as well as grip strength measurements (GSM) and voluntary running exercise at different timepoints, including in-vitro fatigability and force of the EDL and soleus muscles. All groups were randomized, and data collection performed in a blinded fashion.
Results: Bodyweight was unaffected by treatments compared to mdx vehicle. GSM for Ruxolitinib 45 mg/kg was significantly higher compared to mdx vehicle at treatment week 5, but not at treatment week 10. Treatment with Tofacitinib showed no improvements. Voluntary running exercise decreased significantly at treatment week 6 for Ruxolitinib 90 mg/kg; and at treatment week 11 for both Ruxolitinib 45 and 90mg/kg compared to mdx vehicle; suggesting that this drug affected voluntary wheel running negatively. In vitro in EDL and soleus muscles showed no differences between mdx vehicle and mdx-treated groups for fatigue, maximal and specific force.
Conclusion: Treatment of mdx mice with both Ruxolitinib and Tofacitinib did not improve functional and behavioral assessments. Instead, treatment with Ruxolitinib showed negative effects in voluntary running exercise.