Journal
BIOMOLECULES
Volume 11, Issue 11, Pages -Publisher
MDPI
DOI: 10.3390/biom11111742
Keywords
Duchenne muscular dystrophy; preclinical study; mdx mouse; dasatinib; cyclodextrin; oral formulation; pediatric age
Categories
Funding
- Dutch Duchenne Parent Project (DPP NL) 2015 Grant entitled Preclinical studies to validate cSrc tyrosine kinase as therapeutic target in Duchenne muscular dystrophy
- PRIN-MIUR (Research Projects of Relevant National Interest-Ministry of Education, University and Research) [2017FJSM9S_005]
- MIUR funding PON (National Operational Program) Research and Innovation 2014-2020 AIM (Attraction and International Mobility) project [AIM1801289-2]
- Research for Innovation (REFIN) POR PUGLIA FESR-FSE 2014-2020 funding [D908ACB4, 50646C43]
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The study showed that a new oral DAS/HP-beta-CD complex efficiently distributed in mdx mice plasma and tissues in a dose-related fashion, reducing beta-DG phosphorylation and restoring its levels dose-dependently in both diaphragm and gastrocnemius muscle. However, although there was modest improvement in in vivo neuromuscular function, ex vivo muscle force, and histopathology, there was partial recovery of muscle elasticity and a decrease of CK and LDH plasma levels, suggesting an increased sarcolemmal stability of dystrophic muscles. Further research is needed to understand the limitations of DAS effectiveness in dystrophic settings and its potential synergy with dystrophin-based molecular therapies.
ROS-activated cSrc tyrosine kinase (TK) promotes the degradation of beta-dystroglycan (beta-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 beta-DG, with minimal amelioration of morphofunctional indices. To address possible dose/pharmacokinetic (PK) issues, a new oral DAS/hydroxypropyl(HP)-beta-cyclodextrin(CD) complex was developed and chronically administered to mdx mice. The aim was to better assess the role of beta-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-beta-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-beta-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 beta-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 beta-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.
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