?url_ver=Z39.88-2004&rft_id=2021-030&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Adc&rft.relation=http%3A%2F%2Frepositorio.uneatlantico.es%2Fid%2Feprint%2F2316%2F&rft.canonical=http%3A%2F%2Frepositorio.uneatlantico.es%2Fid%2Feprint%2F2316%2F&rft.title=An%C3%A1lisis+precl%C3%ADnica+de+nuevos+tratamientos+combinados+para+la+atrofia+muscular+espinal%3A+efectos+sobre+la+supervivencia+de+la+motoneurona%2C+la+integridad+sin%C3%A1ptica+y+la+preservaci%C3%B3n+del+m%C3%BAsculo+esquel%C3%A9tico&rft.creator=%2C+IRBLleida&rft.creator=%2C+US&rft.subject=Biomedicina&rft.subject=Ingenier%C3%ADa&rft.description=Background%2Fmain+objectives%3A+Spinal+muscular+atrophy+(SMA)+is+a+devastating+neuromuscular+disease+characterized+by+degeneration+of+spinal+cord+motoneurons+(MNs)%2C+muscle+weakness%2C+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%2C+a+second+duplicate+gene+(SMN2)+produces+little+and+insufficient+functional+SMN.+Since+the+discovery+of+the+SMN1+gene%2C+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%2C+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%0Anew+approaches+change+the+phenotype+and+analyze+in+detail+their+impact+on+five+hallmarks+of+the+disease%2C+i.e.%2C+MN+deafferentation%2C+spinal+cord+neuroinflammation%2C+MN+alterations+in+autophagy%2C+neuromuscular+junction+neurotransmission+deficiency%2C+and+skeletal+muscle+structural+alterations.%0AMethodology%3A+In+vivo+experiments+will+be+conducted+in+mouse+models+of+SMA%2C+which+will+be+subjected+to+different+single+or+combined+treatments%3B+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%2C+western+blot%2C+and+conventional+and+pre-+and+post-embedding%0Aimmunogold+electron+microscopy+studies+will+be+also+performed.+Additionally%2C+electrophysiological+recordings+of+endplate+potentials+will+be+conducted.%0AExpected+results%3A+We+expect+that+the+use+of+SMN-independent+strategies+in+combination+with+nusinersen+will+help+to+ameliorate+the+neuromuscular+and+systemic+alterations+in+SMA.&rft.publisher=Repositorio+de+la+Universidad&rft.date=2021&rft.type=Otro&rft.type=NonPeerReviewed&rft.identifier=++Otro+Materias+%3E+Biomedicina+%3Chttp%3A%2F%2Frepositorio.uneatlantico.es%2Fview%2Fsubjects%2Funeat%3D5Fbm.html%3E%0AMaterias+%3E+Ingenier%C3%ADa+%3Chttp%3A%2F%2Frepositorio.uneatlantico.es%2Fview%2Fsubjects%2Funeat%3D5Feng.html%3E+Universidad+Europea+del+Atl%C3%A1ntico+%3E+Investigaci%C3%B3n+%3E+Proyectos+I%2BD%2BI+%3Chttp%3A%2F%2Frepositorio.uneatlantico.es%2Fview%2Fdivisions%2Funeatlantico%3D5Fproyectos.html%3E+Cerrado+Espa%C3%B1ol+Background%2Fmain+objectives%3A+Spinal+muscular+atrophy+(SMA)+is+a+devastating+neuromuscular+disease+characterized+by+degeneration+of+spinal+cord+motoneurons+(MNs)%2C+muscle+weakness%2C+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%2C+a+second+duplicate+gene+(SMN2)+produces+little+and+insufficient+functional+SMN.+Since+the+discovery+of+the+SMN1+gene%2C+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%2C+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%2C+i.e.%2C+MN+deafferentation%2C+spinal+cord+neuroinflammation%2C+MN+alterations+in+autophagy%2C+neuromuscular+junction+neurotransmission+deficiency%2C+and+skeletal+muscle+structural+alterations.+Methodology%3A+In+vivo+experiments+will+be+conducted+in+mouse+models+of+SMA%2C+which+will+be+subjected+to+different+single+or+combined+treatments%3B+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+co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