DMD – ANIMAL MODELS & PRECLINICAL TREATMENT: P.211 Src tyrosine kinase as potential target in Duchenne muscular dystrophy: assessment of a novel dasatinib formulation in the mdx mouse model

Abstract

The overexpression and the increased activity of redox-sensitive protein Src-Tyrosine Kinase (TK) in dystrophin-deficient muscles can contribute to β-dystroglycan (β-DG) degradation and in reinforcing proinflammatory damaging signalling. According to the hypothesis that Src-TK is a feasible drug target for ameliorating Duchenne Muscular Dystrophy (DMD), we have recently focused on preclinical studies for repurposing dasatinib, a Src-TK's competitive inhibitor. We have shown that a 4-week subcutaneous treatment with dasatinib (5mg/kg, 3 times/week) induced an increment in β-DG at muscle level, although a parallel limited efficacy on pathology-related functional, structural and biochemical indices was observed. Considering the occurrence of possible pharmacokinetic or time related issues, we presently tested in mdx mouse a new oral formulation (dasatinib-hydroxypropyl-β-cyclodextrin inclusion complex), administered at 10 or 20mg/kg for 12 weeks, in drinking water. The new formulation allowed the drug to reach plasma, liver and skeletal muscle level in a dose-related fashion. Our results showed that, in vivo, dasatinib contrasted the impaired exercise performance during an exhaustion treadmill test, with a recovery score (R.S.) toward WT value of 28% (10mg/kg) and 17% (20mg/kg), but did not exert any effect on mdx mice weakness, assessed by forelimb grip test. Ex vivo, dasatinib ameliorated tetanic isometric force of fast-twitch extensor digitorum longus muscle, with a R.S. of 31% for both doses, while at 10mg/kg it increased tetanic isometric force of diaphragm muscle (R.S. 45%), and partially recovered the elastic properties of this latter during eccentric contraction. Moreover, dasatinib, either 10 or 20mg/kg, notably decreased plasma levels of pathology-related biomarkers creatine kinase (R.S. 28% and 47%) and lactate dehydrogenase (R.S. 36% and 46%). These preliminary data support the interest of this new oral dasatinib formulation for DMD treatment. However, further experiments are needed in order to better establish the therapeutic value of dasatinib in the light of a future repurposing as potential treatment for DMD patients.