β-Dystroglycan Restoration and Pathology Progression in the Dystrophic <i>mdx</i> Mouse: Outcome and Implication of a Clinically Oriented Study with a Novel Oral Dasatinib Formulation
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 <i>mdx</i> m...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-11-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/11/11/1742 |
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| author | Paola Mantuano Brigida Boccanegra Elena Conte Michela De Bellis Santa Cirmi Francesca Sanarica Ornella Cappellari Ilaria Arduino Annalisa Cutrignelli Angela Assunta Lopedota Antonietta Mele Nunzio Denora Annamaria De Luca |
| author_facet | Paola Mantuano Brigida Boccanegra Elena Conte Michela De Bellis Santa Cirmi Francesca Sanarica Ornella Cappellari Ilaria Arduino Annalisa Cutrignelli Angela Assunta Lopedota Antonietta Mele Nunzio Denora Annamaria De Luca |
| author_sort | Paola Mantuano |
| collection | DOAJ |
| description | 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 <i>mdx</i> 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 <i>mdx</i> 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 <i>mdx</i> 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 <i>mdx</i> 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. |
| first_indexed | 2024-03-10T05:40:17Z |
| format | Article |
| id | doaj.art-68d8ae6534034deeb1e5c4e403792037 |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-10T05:40:17Z |
| publishDate | 2021-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-68d8ae6534034deeb1e5c4e4037920372023-11-22T22:35:40ZengMDPI AGBiomolecules2218-273X2021-11-011111174210.3390/biom11111742β-Dystroglycan Restoration and Pathology Progression in the Dystrophic <i>mdx</i> Mouse: Outcome and Implication of a Clinically Oriented Study with a Novel Oral Dasatinib FormulationPaola Mantuano0Brigida Boccanegra1Elena Conte2Michela De Bellis3Santa Cirmi4Francesca Sanarica5Ornella Cappellari6Ilaria Arduino7Annalisa Cutrignelli8Angela Assunta Lopedota9Antonietta Mele10Nunzio Denora11Annamaria De Luca12Section of Pharmacology, Department of Pharmacy—Drug Sciences, Orabona 4—Campus, University of Bari “Aldo Moro”, 70125 Bari, ItalySection of Pharmacology, Department of Pharmacy—Drug Sciences, Orabona 4—Campus, University of Bari “Aldo Moro”, 70125 Bari, ItalySection of Pharmacology, Department of Pharmacy—Drug Sciences, Orabona 4—Campus, University of Bari “Aldo Moro”, 70125 Bari, ItalySection of Pharmacology, Department of Pharmacy—Drug Sciences, Orabona 4—Campus, University of Bari “Aldo Moro”, 70125 Bari, ItalySection of Pharmacology, Department of Pharmacy—Drug Sciences, Orabona 4—Campus, University of Bari “Aldo Moro”, 70125 Bari, ItalySection of Pharmacology, Department of Pharmacy—Drug Sciences, Orabona 4—Campus, University of Bari “Aldo Moro”, 70125 Bari, ItalySection of Pharmacology, Department of Pharmacy—Drug Sciences, Orabona 4—Campus, University of Bari “Aldo Moro”, 70125 Bari, ItalySection of Pharmaceutical Technologies, Department of Pharmacy—Drug Sciences, Orabona 4—Campus, University of Bari “Aldo Moro”, 70125 Bari, ItalySection of Pharmaceutical Technologies, Department of Pharmacy—Drug Sciences, Orabona 4—Campus, University of Bari “Aldo Moro”, 70125 Bari, ItalySection of Pharmaceutical Technologies, Department of Pharmacy—Drug Sciences, Orabona 4—Campus, University of Bari “Aldo Moro”, 70125 Bari, ItalySection of Pharmacology, Department of Pharmacy—Drug Sciences, Orabona 4—Campus, University of Bari “Aldo Moro”, 70125 Bari, ItalySection of Pharmaceutical Technologies, Department of Pharmacy—Drug Sciences, Orabona 4—Campus, University of Bari “Aldo Moro”, 70125 Bari, ItalySection of Pharmacology, Department of Pharmacy—Drug Sciences, Orabona 4—Campus, University of Bari “Aldo Moro”, 70125 Bari, ItalyROS-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 <i>mdx</i> 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 <i>mdx</i> 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 <i>mdx</i> 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 <i>mdx</i> 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.https://www.mdpi.com/2218-273X/11/11/1742Duchenne muscular dystrophypreclinical study<i>mdx</i> mousedasatinibcyclodextrinoral formulation |
| spellingShingle | Paola Mantuano Brigida Boccanegra Elena Conte Michela De Bellis Santa Cirmi Francesca Sanarica Ornella Cappellari Ilaria Arduino Annalisa Cutrignelli Angela Assunta Lopedota Antonietta Mele Nunzio Denora Annamaria De Luca β-Dystroglycan Restoration and Pathology Progression in the Dystrophic <i>mdx</i> Mouse: Outcome and Implication of a Clinically Oriented Study with a Novel Oral Dasatinib Formulation Biomolecules Duchenne muscular dystrophy preclinical study <i>mdx</i> mouse dasatinib cyclodextrin oral formulation |
| title | β-Dystroglycan Restoration and Pathology Progression in the Dystrophic <i>mdx</i> Mouse: Outcome and Implication of a Clinically Oriented Study with a Novel Oral Dasatinib Formulation |
| title_full | β-Dystroglycan Restoration and Pathology Progression in the Dystrophic <i>mdx</i> Mouse: Outcome and Implication of a Clinically Oriented Study with a Novel Oral Dasatinib Formulation |
| title_fullStr | β-Dystroglycan Restoration and Pathology Progression in the Dystrophic <i>mdx</i> Mouse: Outcome and Implication of a Clinically Oriented Study with a Novel Oral Dasatinib Formulation |
| title_full_unstemmed | β-Dystroglycan Restoration and Pathology Progression in the Dystrophic <i>mdx</i> Mouse: Outcome and Implication of a Clinically Oriented Study with a Novel Oral Dasatinib Formulation |
| title_short | β-Dystroglycan Restoration and Pathology Progression in the Dystrophic <i>mdx</i> Mouse: Outcome and Implication of a Clinically Oriented Study with a Novel Oral Dasatinib Formulation |
| title_sort | β dystroglycan restoration and pathology progression in the dystrophic i mdx i mouse outcome and implication of a clinically oriented study with a novel oral dasatinib formulation |
| topic | Duchenne muscular dystrophy preclinical study <i>mdx</i> mouse dasatinib cyclodextrin oral formulation |
| url | https://www.mdpi.com/2218-273X/11/11/1742 |
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