β-Dystroglycan Restoration and Pathology Progression in the Dystrophic mdx Mouse: Outcome and Implication of a Clinically Oriented Study with a Novel Oral Dasatinib Formulation.
Paola MantuanoBrigida BoccanegraElena ConteMichela De BellisSanta CirmiFrancesca SanaricaOrnella CappellariIlaria ArduinoAnnalisa CutrignelliAngela Assunta LopedotaAntonietta MeleNunzio DenoraAnnamaria De LucaPublished in: Biomolecules (2021)
ROS-activated cSrc tyrosine kinase (TK) promotes the degradation of β-dystroglycan (β-DG), a dystrophin-glycoprotein complex component, which may reinforce damaging signals in Duchenne muscular dystrophy (DMD). Therefore, cSrc-TK represents a promising therapeutic target. In mdx mice, a 4-week subcutaneous treatment with dasatinib (DAS), a pan-Src-TKs inhibitor approved as anti-leukemic agent, increased muscle β-DG, with minimal amelioration of morphofunctional indices. To address possible dose/pharmacokinetic (PK) issues, a new oral DAS/hydroxypropyl(HP)-β-cyclodextrin(CD) complex was developed and chronically administered to mdx mice. The aim was to better assess the role of β-DG in pathology progression, meanwhile confirming DAS mechanism of action over the long-term, along with its efficacy and tolerability. The 4-week old mdx mice underwent a 12-week treatment with DAS/HP-β-CD10% dissolved in drinking water, at 10 or 20 mg/kg/day. The outcome was evaluated via in vivo/ex vivo disease-relevant readouts. Oral DAS/HP-β-CD efficiently distributed in mdx mice plasma and tissues in a dose-related fashion. The new DAS formulation confirmed its main upstream mechanism of action, by reducing β-DG phosphorylation and restoring its levels dose-dependently in both diaphragm and gastrocnemius muscle. However, it modestly improved in vivo neuromuscular function, ex vivo muscle force, and histopathology, although the partial recovery of muscle elasticity and the decrease of CK and LDH plasma levels suggest an increased sarcolemmal stability of dystrophic muscles. Our clinically oriented study supports the interest in this new, pediatric-suitable DAS formulation for proper exposure and safety and for enhancing β-DG expression. This latter mechanism is, however, not sufficient by itself to impact on pathology progression. In-depth analyses will be dedicated to elucidating the mechanism limiting DAS effectiveness in dystrophic settings, meanwhile assessing its potential synergy with dystrophin-based molecular therapies.
Keyphrases
- duchenne muscular dystrophy
- disease activity
- tyrosine kinase
- rheumatoid arthritis
- systemic lupus erythematosus
- drinking water
- high fat diet induced
- skeletal muscle
- muscular dystrophy
- drug delivery
- randomized controlled trial
- systematic review
- poor prognosis
- epidermal growth factor receptor
- insulin resistance
- health risk
- acute myeloid leukemia
- combination therapy
- gene expression
- intensive care unit
- wild type
- heavy metals
- single molecule
- study protocol
- oxidative stress
- reactive oxygen species
- adipose tissue
- ionic liquid
- acute respiratory distress syndrome
- capillary electrophoresis