relation: http://repositorio.uneatlantico.es/id/eprint/2316/
canonical: http://repositorio.uneatlantico.es/id/eprint/2316/
title: Análisis preclínica de nuevos tratamientos combinados para la atrofia muscular espinal: efectos sobre la supervivencia de la motoneurona, la integridad sináptica y la preservación del músculo esquelético
creator: , IRBLleida
creator: , US
subject: Biomedicina
subject: Ingeniería
description: Background/main objectives: Spinal muscular atrophy (SMA) is a devastating neuromuscular disease characterized by degeneration of spinal cord motoneurons (MNs), muscle weakness, and severe disability. SMA is the most common genetic disease resulting in infantile death. It is caused by reduction of the survival motor neuron (SMN) protein due to the loss or mutations of SMN1 gene. In humans, a second duplicate gene (SMN2) produces little and insufficient functional SMN. Since the discovery of the SMN1 gene, intensive efforts have been aimed to develop therapies to increase SMN protein levels. The SNM2-directed antisense oligonucleotide nusinersen effectively increases SMN in clinical trials, but its effectiveness varies between individuals and is markedly diminished in post-symptomatic treated patients. We aim to examine here the possible beneficial effect of combining nusinersen with drugs directed to the CNS and peripheral tissues that we previously found to have beneficial in vivo and in vitro effects in SMA models. We will investigate how these new approaches change the phenotype and analyze in detail their impact on five hallmarks of the disease, i.e., MN deafferentation, spinal cord neuroinflammation, MN alterations in autophagy, neuromuscular junction neurotransmission deficiency, and skeletal muscle structural alterations. Methodology: In vivo experiments will be conducted in mouse models of SMA, which will be subjected to different single or combined treatments; motor behavior tests and survival analysis will be performed. In vitro studies will be carried out in SMA mouse MNs and in induced pluripotent stem cell (iPSC) lines from control and SMA patients. Immunocytochemistry, western blot, and conventional and pre- and post-embedding immunogold electron microscopy studies will be also performed. Additionally, electrophysiological recordings of endplate potentials will be conducted. Expected results: We expect that the use of SMN-independent strategies in combination with nusinersen will help to ameliorate the neuromuscular and systemic alterations in SMA.
publisher: Repositorio de la Universidad
date: 2021
type: Otro
type: NonPeerReviewed
identifier:   Otro Materias > Biomedicina <http://repositorio.uneatlantico.es/view/subjects/uneat=5Fbm.html> Materias > Ingeniería <http://repositorio.uneatlantico.es/view/subjects/uneat=5Feng.html> Universidad Europea del Atlántico > Investigación > Proyectos I+D+I <http://repositorio.uneatlantico.es/view/divisions/uneatlantico=5Fproyectos.html> Cerrado Español Background/main objectives: Spinal muscular atrophy (SMA) is a devastating neuromuscular disease characterized by degeneration of spinal cord motoneurons (MNs), muscle weakness, and severe disability. SMA is the most common genetic disease resulting in infantile death. It is caused by reduction of the survival motor neuron (SMN) protein due to the loss or mutations of SMN1 gene. In humans, a second duplicate gene (SMN2) produces little and insufficient functional SMN. Since the discovery of the SMN1 gene, intensive efforts have been aimed to develop therapies to increase SMN protein levels. The SNM2-directed antisense oligonucleotide nusinersen effectively increases SMN in clinical trials, but its effectiveness varies between individuals and is markedly diminished in post-symptomatic treated patients. We aim to examine here the possible beneficial effect of combining nusinersen with drugs directed to the CNS and peripheral tissues that we previously found to have beneficial in vivo and in vitro effects in SMA models. We will investigate how these new approaches change the phenotype and analyze in detail their impact on five hallmarks of the disease, i.e., MN deafferentation, spinal cord neuroinflammation, MN alterations in autophagy, neuromuscular junction neurotransmission deficiency, and skeletal muscle structural alterations. Methodology: In vivo experiments will be conducted in mouse models of SMA, which will be subjected to different single or combined treatments; motor behavior tests and survival analysis will be performed. In vitro studies will be carried out in SMA mouse MNs and in induced pluripotent stem cell (iPSC) lines from control and SMA patients. Immunocytochemistry, western blot, and conventional and pre- and post-embedding immunogold electron microscopy studies will be also performed. Additionally, electrophysiological recordings of endplate potentials will be conducted. Expected results: We expect that the use of SMN-independent strategies in combination with nusinersen will help to ameliorate the neuromuscular and systemic alterations in SMA. metadata , IRBLleida y , US mail SIN ESPECIFICAR       (2021) Análisis preclínica de nuevos tratamientos combinados para la atrofia muscular espinal: efectos sobre la supervivencia de la motoneurona, la integridad sináptica y la preservación del músculo esquelético.  Repositorio de la Universidad.    (Inédito)  
relation: 2021-030
language: es