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...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	Duchenne muscular dystrophy preclinical study <i>mdx</i> mouse dasatinib cyclodextrin oral formulation Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/68d8ae6534034deeb1e5c4e403792037
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:68d8ae6534034deeb1e5c4e403792037
record_format	dspace
spelling	oai:doaj.org-article:68d8ae6534034deeb1e5c4e4037920372021-11-25T16:54:47Zβ-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 Formulation10.3390/biom111117422218-273Xhttps://doaj.org/article/68d8ae6534034deeb1e5c4e4037920372021-11-01T00:00:00Zhttps://www.mdpi.com/2218-273X/11/11/1742https://doaj.org/toc/2218-273XROS-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.Paola MantuanoBrigida BoccanegraElena ConteMichela De BellisSanta CirmiFrancesca SanaricaOrnella CappellariIlaria ArduinoAnnalisa CutrignelliAngela Assunta LopedotaAntonietta MeleNunzio DenoraAnnamaria De LucaMDPI AGarticleDuchenne muscular dystrophypreclinical study<i>mdx</i> mousedasatinibcyclodextrinoral formulationMicrobiologyQR1-502ENBiomolecules, Vol 11, Iss 1742, p 1742 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Duchenne muscular dystrophy preclinical study <i>mdx</i> mouse dasatinib cyclodextrin oral formulation Microbiology QR1-502
spellingShingle	Duchenne muscular dystrophy preclinical study <i>mdx</i> mouse dasatinib cyclodextrin oral formulation Microbiology QR1-502 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
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.
format	article
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
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_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_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_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
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/68d8ae6534034deeb1e5c4e403792037
work_keys_str_mv	AT paolamantuano bdystroglycanrestorationandpathologyprogressioninthedystrophicimdximouseoutcomeandimplicationofaclinicallyorientedstudywithanoveloraldasatinibformulation AT brigidaboccanegra bdystroglycanrestorationandpathologyprogressioninthedystrophicimdximouseoutcomeandimplicationofaclinicallyorientedstudywithanoveloraldasatinibformulation AT elenaconte bdystroglycanrestorationandpathologyprogressioninthedystrophicimdximouseoutcomeandimplicationofaclinicallyorientedstudywithanoveloraldasatinibformulation AT micheladebellis bdystroglycanrestorationandpathologyprogressioninthedystrophicimdximouseoutcomeandimplicationofaclinicallyorientedstudywithanoveloraldasatinibformulation AT santacirmi bdystroglycanrestorationandpathologyprogressioninthedystrophicimdximouseoutcomeandimplicationofaclinicallyorientedstudywithanoveloraldasatinibformulation AT francescasanarica bdystroglycanrestorationandpathologyprogressioninthedystrophicimdximouseoutcomeandimplicationofaclinicallyorientedstudywithanoveloraldasatinibformulation AT ornellacappellari bdystroglycanrestorationandpathologyprogressioninthedystrophicimdximouseoutcomeandimplicationofaclinicallyorientedstudywithanoveloraldasatinibformulation AT ilariaarduino bdystroglycanrestorationandpathologyprogressioninthedystrophicimdximouseoutcomeandimplicationofaclinicallyorientedstudywithanoveloraldasatinibformulation AT annalisacutrignelli bdystroglycanrestorationandpathologyprogressioninthedystrophicimdximouseoutcomeandimplicationofaclinicallyorientedstudywithanoveloraldasatinibformulation AT angelaassuntalopedota bdystroglycanrestorationandpathologyprogressioninthedystrophicimdximouseoutcomeandimplicationofaclinicallyorientedstudywithanoveloraldasatinibformulation AT antoniettamele bdystroglycanrestorationandpathologyprogressioninthedystrophicimdximouseoutcomeandimplicationofaclinicallyorientedstudywithanoveloraldasatinibformulation AT nunziodenora bdystroglycanrestorationandpathologyprogressioninthedystrophicimdximouseoutcomeandimplicationofaclinicallyorientedstudywithanoveloraldasatinibformulation AT annamariadeluca bdystroglycanrestorationandpathologyprogressioninthedystrophicimdximouseoutcomeandimplicationofaclinicallyorientedstudywithanoveloraldasatinibformulation
_version_	1718412841191473152

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

Ejemplares similares