Resultados de la búsqueda125 resultados
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El proceso de desarrollo de fármacos para la distrofia miotónica tipo 1: edición 2022
Pascual-Gilabert M, Artero R, López-Castel A - 2023 - Drug Discov Today
(2023). ArticleThe beginning of the 20th decade has witnessed an increase in drug development programs for myotonic dystrophy type 1 (DM1). We have collected nearly 20 candidate drugs with accomplished preclinical and clinical phases, updating our previous drug development pipeline review with new entries and relevant milestones for pre-existing candidates. Three interventional first-in-human clinical trials got underway with distinct drug classes, namely AOC 1001 and DYNE-101 nucleic acid-based therapies, and the small molecule pitolisant, which joins the race toward market authorization with other repurposed drugs, including tideglusib, metformin, or mexiletine, already in clinical evaluation....
The beginning of the 20th decade has witnessed an increase in drug development programs for myotonic dystrophy type 1 (DM1). We have collected nearly 20 candidate drugs with accomplished preclinical and clinical phases, updating our previous drug development pipeline review with new entries and relevant milestones for pre-existing candidates. Three interventional first-in-human clinical trials got underway with distinct drug classes, namely AOC 1001 and DYNE-101 nucleic acid-based therapies, and the small molecule pitolisant, which joins the race toward market authorization with other repurposed drugs, including tideglusib, metformin, or mexiletine, already in clinical evaluation. Furthermore, newly disclosed promising preclinical data for several additional nucleic-acid therapeutic candidates and a CRISPR-based approach, as well as the advent into the pipeline of novel therapeutic programs, increase the plausibility of success in the demanding task of providing valid treatments to patients with DM1. Keywords: CTG repeat expansion; clinical trial; drug development; drug repurposing; gene therapy; myotonic dystrophy; nucleic acids therapeutics; small molecule.
Leer más Ocultar DOI: 10.1016/j.drudis.2023.103489 -
Desarrollo de potentes aglutinantes de ADN tripodales G-quadruplex y su administración eficiente a células cancerosas mediante liposomas funcionalizados con aptámeros
Pont I, Galiana-Roselló C, Sabater-Arcis M, Bargiela A, Frías JC, Albelda MT, González-García J, García-España E - 2023 - Org Biomol Chem
(2023). ArticleTwo new ligands (TPB3P and TPB3Py) showing a strong stabilisation effect and good selectivity for G4 over duplex DNAs have been synthesised. The ligands hold three analogous polyamine pendant arms (TPA3P and TPA3Py) but differ in the central aromatic core, which is a triphenylbenzene moiety instead of a triphenylamine moiety. Both TPB3P and TPB3Py exhibit high cytotoxicity in MCF-7, LN229 and HeLa cancer cells in contrast to TPA-based ligands, which exhibit no significant cytotoxicity. Moreover, the most potent G4 binders have been encapsulated in liposomes and AS1411 aptamer-targeted liposomes reaching nanomolar IC50 values for the most cytotoxic systems.
DOI: 10.1039/d2ob01911f -
Edición CRISPR-Cas9 de una mutación TNPO3 en un modelo de células musculares de distrofia muscular de cinturas tipo D2
Poyatos-García J, Blázquez-Bernal Á, Selva-Giménez M, Bargiela A, Espinosa-Espinosa J, Vázquez-Manrique RP, Bigot A, Artero R, Vilchez JJ - 2023 - Mol Ther Nucleic Acids
(2023). ArticleA single-nucleotide deletion in the stop codon of the nuclear import receptor transportin-3 (TNPO3), also involved in human immunodeficiency virus type 1 (HIV-1) infection, causes the ultrarare autosomal dominant disease limb-girdle muscular dystrophy D2 (LGMDD2) by extending the wild-type protein. Here, we generated a patient-derived in vitro model of LGMDD2 as an immortalized myoblast cell line carrying the TNP O 3 mutation. The cell model reproduced critical molecular alterations seen in patients, such as TNP O 3 overexpression, defects in terminal muscle markers, and autophagy overactivation. Correction of the TNP O 3 mutation via CRISPR-Cas9 editing caused a significant reversion of...
A single-nucleotide deletion in the stop codon of the nuclear import receptor transportin-3 (TNPO3), also involved in human immunodeficiency virus type 1 (HIV-1) infection, causes the ultrarare autosomal dominant disease limb-girdle muscular dystrophy D2 (LGMDD2) by extending the wild-type protein. Here, we generated a patient-derived in vitro model of LGMDD2 as an immortalized myoblast cell line carrying the TNP O 3 mutation. The cell model reproduced critical molecular alterations seen in patients, such as TNP O 3 overexpression, defects in terminal muscle markers, and autophagy overactivation. Correction of the TNP O 3 mutation via CRISPR-Cas9 editing caused a significant reversion of the pathological phenotypes in edited cells, including a complete absence of the mutant TNPO3 protein, as detected with a polyclonal antibody specific against the abnormal 15-aa peptide. Transcriptomic analyses found that 15% of the transcriptome was differentially expressed in model myotubes. CRISPR-Cas9-corrected cells showed that 44% of the alterations were rescued toward normal levels. MicroRNAs (miRNAs) analyses showed that around 50% of miRNAs with impaired expression because of the disease were recovered on the mutation edition. In summary, this work provides proof of concept of the potential of CRISPR-Cas9-mediated gene editing of TNP O 3 as a therapeutic approach and describes critical reagents in LGMDD2 research. Keywords: CRISPR; LGMDD2; MT: RNA/DNA Editing; TNPO3; autophagy; cellular model; gene editing; muscle dysfunction; myoblast; myopathy.
Leer más Ocultar DOI: 10.1016/j.omtn.2023.01.004 -
Quantitative magnetic resonance imaging assessment of muscle composition in myotonic dystrophy mice
Bargiela A, Ten-Esteve A, Martí-Bonmatí L, Sevilla T, Perez Alonso M, Artero R - 2023 - Sci Rep
(2023). ArticleMyotonic dystrophy type 1 (DM1) is a severe autosomal dominant neuromuscular disease in which the musculoskeletal system contributes substantially to overall mortality and morbidity. DM1 stems from a noncoding CTG trinucleotide repeat expansion in the DMPK gene. The human skeletal actin long repeat (HSALR) mouse model reproduces several aspects of the disease, but the muscle-wasting phenotype of this model has never been characterized in vivo. Herein, we used quantitative MRI to measure the fat and muscle volumes in the leg compartment (LC) of mice. These acquired data were processed to extract relevant parameters such as fat fraction and fat infiltration (fat LC/LC) in HSALR and control...
Myotonic dystrophy type 1 (DM1) is a severe autosomal dominant neuromuscular disease in which the musculoskeletal system contributes substantially to overall mortality and morbidity. DM1 stems from a noncoding CTG trinucleotide repeat expansion in the DMPK gene. The human skeletal actin long repeat (HSALR) mouse model reproduces several aspects of the disease, but the muscle-wasting phenotype of this model has never been characterized in vivo. Herein, we used quantitative MRI to measure the fat and muscle volumes in the leg compartment (LC) of mice. These acquired data were processed to extract relevant parameters such as fat fraction and fat infiltration (fat LC/LC) in HSALR and control (FBV) muscles. These results showed increased fat volume (fat LC) and fat infiltration within the muscle tissue of the leg compartment (muscle LC), in agreement with necropsies, in which fatty clumps were observed, and consistent with previous findings in DM1 patients. Model mice did not reproduce the characteristic impaired fat fraction, widespread fat replacement through the muscles, or reduced muscle volume reported in patients. Taken together, the observed abnormal replacement of skeletal muscle by fat in the HSALR mice indicates that these mice partially reproduced the muscle phenotype observed in humans.
Leer más Ocultar DOI: 10.1038/s41598-023-27661-w -
Direct TLR2 signaling through mTOR and TBK1 induces C/EBPβ and IRF7-dependent macrophage differentiation in hematopoietic stem and progenitor cells
Bono, C., Guerrero, P., Erades, A., Jordán-Pla, A., Yáñez, A and Gil, M.L.
(2022). ArticleStem Cells.
21;40(10):949-962
Categoría: “Biotechnology & Applied Microbiology”, Posición: 32/156 (Q1), F.I.: 5.2 (2022)
DOI: 10.1093/stmcls/sxac053
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Moxifloxacin rescues SMA phenotypes in patient-derived cells and animal model
Januel C, Menduti G, Mamchaoui K, Martinat C, Artero R, Konieczny P, Boido M - 2022 - Cell Mol Life Sci
(2022). ArticleSpinal muscular atrophy (SMA) is a genetic disease resulting in the loss of α-motoneurons followed by muscle atrophy. It is caused by knock-out mutations in the survival of motor neuron 1 (SMN1) gene, which has an unaffected, but due to preferential exon 7 skipping, only partially functional human-specific SMN2 copy. We previously described a Drosophila-based screening of FDA-approved drugs that led us to discover moxifloxacin. We showed its positive effect on the SMN2 exon 7 splicing in SMA patient-derived skin cells and its ability to increase the SMN protein level. Here, we focus on moxifloxacin's therapeutic potential in additional SMA cellular and animal models. We demonstrate that...
Spinal muscular atrophy (SMA) is a genetic disease resulting in the loss of α-motoneurons followed by muscle atrophy. It is caused by knock-out mutations in the survival of motor neuron 1 (SMN1) gene, which has an unaffected, but due to preferential exon 7 skipping, only partially functional human-specific SMN2 copy. We previously described a Drosophila-based screening of FDA-approved drugs that led us to discover moxifloxacin. We showed its positive effect on the SMN2 exon 7 splicing in SMA patient-derived skin cells and its ability to increase the SMN protein level. Here, we focus on moxifloxacin's therapeutic potential in additional SMA cellular and animal models. We demonstrate that moxifloxacin rescues the SMA-related molecular and phenotypical defects in muscle cells and motoneurons by improving the SMN2 splicing. The consequent increase of SMN levels was higher than in case of risdiplam, a potent exon 7 splicing modifier, and exceeded the threshold necessary for a survival improvement. We also demonstrate that daily subcutaneous injections of moxifloxacin in a severe SMA murine model reduces its characteristic neuroinflammation and increases the SMN levels in various tissues, leading to improved motor skills and extended lifespan. We show that moxifloxacin, originally used as an antibiotic, can be potentially repositioned for the SMA treatment. Keywords: Drug repurposing; Motoneurons; SMA delta7 mice; SMN2 splicing; Spinal muscular atrophy.
Leer más Ocultar DOI: 10.1007/s00018-022-04450-8 -
Heterogeneity and origins of myeloid cells
Yáñez, A., Bono, C., Goodridge, H.S
(2022). ArticleCurrent Opinion in Hematology.
1;29(4):201-208.
Categoría: “Hematology”, Posición: 37/79 (Q2), F.I.: 3.2 (2022)
DOI: 10.1097/MOH.0000000000000716
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Rapid Determination of MBNL1 Protein Levels by Quantitative Dot Blot for the Evaluation of Antisense Oligonucleotides in Myotonic Dystrophy Myoblasts
Moreno N, González-Martínez I, Artero R, Cerro-Herreros E - 2022 - Methods Mol Biol
(2022). ArticleWestern blot assays are not adequate for high-throughput screening of protein expression because it is an expensive and time-consuming technique. Here we demonstrate that quantitative dot blots in plate format are a better option to determine the absolute contents of a given protein in less than 48 h. The method was optimized for the detection of the Muscleblind-like 1 protein in patient-derived myoblasts treated with a collection of more than 100 experimental oligonucleotides.
DOI: 10.1007/978-1-0716-2010-6_13 -
Proof of concept of peptide-linked blockmiR-induced MBNL functional rescue in myotonic dystrophy type 1 mouse model
Overby SJ, Cerro-Herreros E, González-Martínez I, Varela MA, Seoane-Miraz D, Jad Y, Raz R, Møller T, Pérez-Alonso M, Wood MJ, Llamusí B, Artero R - 2022 - Mol Ther Nucleic Acids
(2022). ArticleMyotonic dystrophy type 1 is a debilitating neuromuscular disease causing muscle weakness, myotonia, and cardiac dysfunction. The phenotypes are caused by muscleblind-like (MBNL) protein sequestration by toxic RNA in the DM1 protein kinase (DMPK) gene. DM1 patients exhibit a pathogenic number of repetitions in DMPK, which leads to downstream symptoms. Another disease characteristic is altered microRNA (miRNA) expression. It was previously shown that miR-23b regulates the translation of MBNL1 into protein. Antisense oligonucleotide (AON) treatment targeting this miRNA can improve disease symptoms. Here, we present a refinement of this strategy targeting a miR-23b binding site on the MBNL1 3'...
Myotonic dystrophy type 1 is a debilitating neuromuscular disease causing muscle weakness, myotonia, and cardiac dysfunction. The phenotypes are caused by muscleblind-like (MBNL) protein sequestration by toxic RNA in the DM1 protein kinase (DMPK) gene. DM1 patients exhibit a pathogenic number of repetitions in DMPK, which leads to downstream symptoms. Another disease characteristic is altered microRNA (miRNA) expression. It was previously shown that miR-23b regulates the translation of MBNL1 into protein. Antisense oligonucleotide (AON) treatment targeting this miRNA can improve disease symptoms. Here, we present a refinement of this strategy targeting a miR-23b binding site on the MBNL1 3' UTR in DM1 model cells and mice by using AONs called blockmiRs. BlockmiRs linked to novel cell-penetrating peptide chemistry showed an increase in MBNL1 protein in DM1 model cells and HSALR mice. They also showed an increase in muscle strength and significant rescue of downstream splicing and histological phenotypes in mice without disturbing the endogenous levels of other miR-23b target transcripts.
Leer más Ocultar DOI: 10.1016/j.omtn.2022.02.003 -
Deciphering the Complex Molecular Pathogenesis of Myotonic Dystrophy Type 1 through Omics Studies
Espinosa-Espinosa J, González-Barriga A, López-Castel A, Artero R - 2022 - Int J Mol Sci
(2022). ArticleOmics studies are crucial to improve our understanding of myotonic dystrophy type 1 (DM1), the most common muscular dystrophy in adults. Employing tissue samples and cell lines derived from patients and animal models, omics approaches have revealed the myriad alterations in gene and microRNA expression, alternative splicing, 3' polyadenylation, CpG methylation, and proteins levels, among others, that contribute to this complex multisystem disease. In addition, omics characterization of drug candidate treatment experiments provides crucial insight into the degree of therapeutic rescue and off-target effects that can be achieved. Finally, several innovative technologies such as single-cell...
Omics studies are crucial to improve our understanding of myotonic dystrophy type 1 (DM1), the most common muscular dystrophy in adults. Employing tissue samples and cell lines derived from patients and animal models, omics approaches have revealed the myriad alterations in gene and microRNA expression, alternative splicing, 3' polyadenylation, CpG methylation, and proteins levels, among others, that contribute to this complex multisystem disease. In addition, omics characterization of drug candidate treatment experiments provides crucial insight into the degree of therapeutic rescue and off-target effects that can be achieved. Finally, several innovative technologies such as single-cell sequencing and artificial intelligence will have a significant impact on future DM1 research.
Leer más Ocultar DOI: 10.3390/ijms23031441
