Src tyrosine kinase as potential drug target in Duchenne muscular dystrophy: in vivo and in vitro preclinical studies

2017 ◽  
Vol 27 ◽  
pp. S192
Author(s):  
F. Sanarica ◽  
P. Mantuano ◽  
A. Cozzoli ◽  
R. Capogrosso ◽  
N. Denora ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Tyrosine Kinase ◽  
Drug Target ◽  
Preclinical Studies ◽  
Potential Drug Target ◽  
Potential Drug ◽  
Src Tyrosine Kinase

scholarly journals A causal role for TRESK loss of function in migraine mechanisms

Brain ◽  
2019 ◽  
Vol 142 (12) ◽  
pp. 3852-3867 ◽  
Author(s):  
Philippa Pettingill ◽  
Greg A Weir ◽  
Tina Wei ◽  
Yukyee Wu ◽  
Grace Flower ◽  
...  
Keyword(s):  
Potassium Channel ◽  
Drug Target ◽  
Causal Role ◽  
Potential Drug Target ◽  
Potential Drug ◽  
Loss Of Function

The two-pore potassium channel TRESK is a potential drug target in pain and migraine. Pettingill et al. show that the F139WfsX2 mutation causes TRESK loss of function and hyperexcitability in nociceptors derived from iPSCs of patients with migraine. Cloxyquin, a TRESK activator, reverses migraine-relevant phenotypes in vitro and in vivo.

scholarly journals Applications of CRISPR/Cas9 for the Treatment of Duchenne Muscular Dystrophy

2018 ◽  
Vol 8 (4) ◽  
pp. 38 ◽  
Author(s):  
Kenji Lim ◽  
Chantal Yoon ◽  
Toshifumi Yokota
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Wide Spectrum ◽  
Membrane Integrity ◽  
Dystrophin Gene ◽  
Muscle Membrane ◽  
Reading Frame ◽  
Long Term Treatment

Duchenne muscular dystrophy (DMD) is a fatal X-linked recessive neuromuscular disease prevalent in 1 in 3500 to 5000 males worldwide. As a result of mutations that interrupt the reading frame of the dystrophin gene (DMD), DMD is characterized by a loss of dystrophin protein that leads to decreased muscle membrane integrity, which increases susceptibility to degeneration. CRISPR/Cas9 technology has garnered interest as an avenue for DMD therapy due to its potential for permanent exon skipping, which can restore the disrupted DMD reading frame in DMD and lead to dystrophin restoration. An RNA-guided DNA endonuclease system, CRISPR/Cas9 allows for the targeted editing of specific sequences in the genome. The efficacy and safety of CRISPR/Cas9 as a therapy for DMD has been evaluated by numerous studies in vitro and in vivo, with varying rates of success. Despite the potential of CRISPR/Cas9-mediated gene editing for the long-term treatment of DMD, its translation into the clinic is currently challenged by issues such as off-targeting, immune response activation, and sub-optimal in vivo delivery. Its nature as being mostly a personalized form of therapy also limits applicability to DMD patients, who exhibit a wide spectrum of mutations. This review summarizes the various CRISPR/Cas9 strategies that have been tested in vitro and in vivo for the treatment of DMD. Perspectives on the approach will be provided, and the challenges faced by CRISPR/Cas9 in its road to the clinic will be briefly discussed.

Nintedanib as a new therapeutic agent for Duchenne muscular dystrophy: preclinical in vitro and in vivo studies

2017 ◽  
Vol 27 ◽  
pp. S191
Author(s):  
P. Piñol ◽  
E. Fernández-Simón ◽  
X. Suárez ◽  
N. de Luna ◽  
A. Molins ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Therapeutic Agent ◽  
In Vivo Studies

scholarly journals Biosynthesis of the redox cofactor mycofactocin comprises oligoglycosylation by MftF in Mycolicibacterium smegmatis

2019 ◽  
Author(s):  
Luis Peña-Ortiz ◽  
Ana Patrícia Graça ◽  
Huijuan Guo ◽  
Daniel Braga ◽  
Tobias G. Köllner ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Metabolic Profiling ◽  
Drug Target ◽  
Structure Elucidation ◽  
Potential Drug Target ◽  
Potential Drug ◽  
Alcohol Metabolism ◽  
Future Studies ◽  
Mycobacterial Diseases

AbstractMycofactocin (MFT) is a redox cofactor involved in alcohol metabolism of mycobacteria including Mycobacterium tuberculosis. In recent years, a preliminary biosynthetic model of MFT has been established by in-vitro studies, while the final structure of MFT remained elusive. Here, we report the discovery of MFT by metabolomics and establish a model of its biosynthesis in Mycolicibacterium smegmatis. Structure elucidation revealed that MFT is decorated with up to nine β-1,4-linked glucose residues. Dissection of biosynthetic genes demonstrated that the oligoglycosylation is catalyzed by the glycosyltransferase MftF. Furthermore, we confirm the cofactor function of MFT by activity-based metabolic profiling using the carveol dehydrogenase LimC and show that the MFT pool expands during cultivation on ethanol. Our results close an important gap of knowledge, will guide future studies into the physiological roles of MFT in bacteria and may inspire its utilization as a biomarker or potential drug target to combat mycobacterial diseases.

scholarly journals Role of proteoglycans and glycosaminoglycans in Duchenne muscular dystrophy

Glycobiology ◽  
2018 ◽  
Vol 29 (2) ◽  
pp. 110-123 ◽  
Author(s):  
Laurino Carmen ◽  
Vadala’ Maria ◽  
Julio Cesar Morales-Medina ◽  
Annamaria Vallelunga ◽  
Beniamino Palmieri ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Mammalian Cells ◽  
Muscle Development ◽  
Glycoprotein Complex ◽  
Experimental Therapies ◽  
Dystrophin Protein

Abstract Duchenne muscular dystrophy (DMD) is an inherited fatal X-linked myogenic disorder with a prevalence of 1 in 3500 male live births. It affects voluntary muscles, and heart and breathing muscles. DMD is characterized by continuous degeneration and regeneration cycles resulting in extensive fibrosis and a progressive reduction in muscle mass. Since the identification of a reduction in dystrophin protein as the cause of this disorder, numerous innovative and experimental therapies, focusing on increasing the levels of dystrophin, have been proposed, but the clinical improvement has been unsatisfactory. Dystrophin forms the dystrophin-associated glycoprotein complex and its proteins have been studied as a promising novel therapeutic target to treat DMD. Among these proteins, cell surface glycosaminoglycans (GAGs) are found almost ubiquitously on the surface and in the extracellular matrix (ECM) of mammalian cells. These macromolecules interact with numerous ligands, including ECM constituents, adhesion molecules and growth factors that play a crucial role in muscle development and maintenance. In this article, we have reviewed in vitro, in vivo and clinical studies focused on the functional role of GAGs in the pathophysiology of DMD with the final aim of summarizing the state of the art of GAG dysregulation within the ECM in DMD and discussing future therapeutic perspectives.

P.315Src tyrosine kinase as a drug target in Duchenne muscular dystrophy: a proof-of-concept study in the exercised mdx mouse

2019 ◽  
Vol 29 ◽  
pp. S159
Author(s):  
F. Sanarica ◽  
B. Boccanegra ◽  
P. Mantuano ◽  
O. Cappellari ◽  
M. De Bellis ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Tyrosine Kinase ◽  
Drug Target ◽  
Mdx Mouse ◽  
Proof Of Concept ◽  
Concept Study

scholarly journals Regulation of Protein Kinase B Tyrosine Phosphorylation by Thyroid-Specific Oncogenic RET/PTC Kinases

2005 ◽  
Vol 19 (11) ◽  
pp. 2748-2759 ◽  
Author(s):  
Hye Sook Jung ◽  
Dong Wook Kim ◽  
Young Suk Jo ◽  
Hyo Kyun Chung ◽  
Jung Hun Song ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Tyrosine Kinase ◽  
Signaling Pathways ◽  
Tyrosine Phosphorylation ◽  
Protein Kinase B ◽  
Cellular Transformation ◽  
Forkhead Transcription Factor ◽  
Src Tyrosine Kinase

Abstract Papillary thyroid carcinoma (PTC) is a heterogenous disorder characterized by unique gene rearrangements and gene mutations that activate signaling pathways responsible for cellular transformation, survival, and antiapoptosis. Activation of protein kinase B (PKB) and its downstream signaling pathways appears to be an important event in thyroid tumorigenesis. In this study, we found that the thyroid-specific oncogenic RET/PTC tyrosine kinase is able to phosphorylate PKB in vitro and in vivo. RET/PTC-transfected cells showed tyrosine phosphorylation of endogenous and exogenous PKB, which was independent of phosphorylation of T308 and S473 regulated by the upstream kinases phosphoinositide-dependent kinase-1 and -2, respectively. The PKB Y315 residue, which is known to be phosphorylated by Src tyrosine kinase, was also a major site of phosphorylation by RET/PTC. RET/PTC-mediated tyrosine phosphorylation results in the activation of PKB kinase activity. The activation of PKB by RET/PTC blocked the activity of the forkhead transcription factor, FKHRL1, but a Y315F mutant of PKB failed to inhibit FKHRL1 activity. In summary, these observations suggest that RET/PTC is able to phosphorylate the Y315 residue of PKB, an event that results in maximal activation of PKB for RET/PTC-induced thyroid tumorigenesis.

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