Cargando…
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...
Autores principales: | , , , , , , , , , , , , |
---|---|
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 |
_version_ | 1784604102899007488 |
---|---|
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. |
format | Online Article Text |
id | pubmed-8615430 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT mantuanopaola bdystroglycanrestorationandpathologyprogressioninthedystrophicmdxmouseoutcomeandimplicationofaclinicallyorientedstudywithanoveloraldasatinibformulation AT boccanegrabrigida bdystroglycanrestorationandpathologyprogressioninthedystrophicmdxmouseoutcomeandimplicationofaclinicallyorientedstudywithanoveloraldasatinibformulation AT conteelena bdystroglycanrestorationandpathologyprogressioninthedystrophicmdxmouseoutcomeandimplicationofaclinicallyorientedstudywithanoveloraldasatinibformulation AT debellismichela bdystroglycanrestorationandpathologyprogressioninthedystrophicmdxmouseoutcomeandimplicationofaclinicallyorientedstudywithanoveloraldasatinibformulation AT cirmisanta bdystroglycanrestorationandpathologyprogressioninthedystrophicmdxmouseoutcomeandimplicationofaclinicallyorientedstudywithanoveloraldasatinibformulation AT sanaricafrancesca bdystroglycanrestorationandpathologyprogressioninthedystrophicmdxmouseoutcomeandimplicationofaclinicallyorientedstudywithanoveloraldasatinibformulation AT cappellariornella bdystroglycanrestorationandpathologyprogressioninthedystrophicmdxmouseoutcomeandimplicationofaclinicallyorientedstudywithanoveloraldasatinibformulation AT arduinoilaria bdystroglycanrestorationandpathologyprogressioninthedystrophicmdxmouseoutcomeandimplicationofaclinicallyorientedstudywithanoveloraldasatinibformulation AT cutrignelliannalisa bdystroglycanrestorationandpathologyprogressioninthedystrophicmdxmouseoutcomeandimplicationofaclinicallyorientedstudywithanoveloraldasatinibformulation AT lopedotaangelaassunta bdystroglycanrestorationandpathologyprogressioninthedystrophicmdxmouseoutcomeandimplicationofaclinicallyorientedstudywithanoveloraldasatinibformulation AT meleantonietta bdystroglycanrestorationandpathologyprogressioninthedystrophicmdxmouseoutcomeandimplicationofaclinicallyorientedstudywithanoveloraldasatinibformulation AT denoranunzio bdystroglycanrestorationandpathologyprogressioninthedystrophicmdxmouseoutcomeandimplicationofaclinicallyorientedstudywithanoveloraldasatinibformulation AT delucaannamaria bdystroglycanrestorationandpathologyprogressioninthedystrophicmdxmouseoutcomeandimplicationofaclinicallyorientedstudywithanoveloraldasatinibformulation |