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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

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 subcu...

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Autores principales: Mantuano, Paola, Boccanegra, Brigida, Conte, Elena, De Bellis, Michela, Cirmi, Santa, Sanarica, Francesca, Cappellari, Ornella, Arduino, Ilaria, Cutrignelli, Annalisa, Lopedota, Angela Assunta, Mele, Antonietta, Denora, Nunzio, De Luca, Annamaria
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8615430/
https://www.ncbi.nlm.nih.gov/pubmed/34827740
http://dx.doi.org/10.3390/biom11111742
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author Mantuano, Paola
Boccanegra, Brigida
Conte, Elena
De Bellis, Michela
Cirmi, Santa
Sanarica, Francesca
Cappellari, Ornella
Arduino, Ilaria
Cutrignelli, Annalisa
Lopedota, Angela Assunta
Mele, Antonietta
Denora, Nunzio
De Luca, Annamaria
author_facet Mantuano, Paola
Boccanegra, Brigida
Conte, Elena
De Bellis, Michela
Cirmi, Santa
Sanarica, Francesca
Cappellari, Ornella
Arduino, Ilaria
Cutrignelli, Annalisa
Lopedota, Angela Assunta
Mele, Antonietta
Denora, Nunzio
De Luca, Annamaria
author_sort Mantuano, Paola
collection PubMed
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 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.
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spelling pubmed-86154302021-11-26 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 Mantuano, Paola Boccanegra, Brigida Conte, Elena De Bellis, Michela Cirmi, Santa Sanarica, Francesca Cappellari, Ornella Arduino, Ilaria Cutrignelli, Annalisa Lopedota, Angela Assunta Mele, Antonietta Denora, Nunzio De Luca, Annamaria Biomolecules Article 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. MDPI 2021-11-22 /pmc/articles/PMC8615430/ /pubmed/34827740 http://dx.doi.org/10.3390/biom11111742 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Mantuano, Paola
Boccanegra, Brigida
Conte, Elena
De Bellis, Michela
Cirmi, Santa
Sanarica, Francesca
Cappellari, Ornella
Arduino, Ilaria
Cutrignelli, Annalisa
Lopedota, Angela Assunta
Mele, Antonietta
Denora, Nunzio
De Luca, Annamaria
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
title 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
title_full 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
title_fullStr 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
title_full_unstemmed 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
title_short 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
title_sort 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
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8615430/
https://www.ncbi.nlm.nih.gov/pubmed/34827740
http://dx.doi.org/10.3390/biom11111742
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