Publication:
MeCP2 gene therapy ameliorates disease phenotype in mouse model for Pitt Hopkins syndrome

cris.virtual.author-orcid0000-0002-7867-9186
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cris.virtual.departmentFacultad de Medicina
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cris.virtualsource.author-orcid4fda5534-6fb2-47fe-a474-d6179b2b387e
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cris.virtualsource.department4fda5534-6fb2-47fe-a474-d6179b2b387e
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dc.contributor.authorDr. Ávila-Macaya, Ariel
dc.contributor.authorDennys, Cassandra
dc.contributor.authorVermudez, Sheryl
dc.contributor.authorDeacon, Robert
dc.contributor.authorSierra-Delgado, J.
dc.contributor.authorRich, Kelly
dc.contributor.authorZhang, Xiaojin
dc.contributor.authorBuch, Aditi
dc.contributor.authorWeiss, Kelly
dc.contributor.authorMoxley, Yuta
dc.contributor.authorRajpal, Hemangi
dc.contributor.authorEspinoza, Francisca
dc.contributor.authorPowers, Samantha
dc.contributor.authorGogliotti, Rocco
dc.contributor.authorCogram, Patricia
dc.contributor.authorNiswender, Colleen
dc.contributor.authorMeyer, Kathrin
dc.date.accessioned2024-11-28T20:24:50Z
dc.date.available2024-11-28T20:24:50Z
dc.date.issued2024
dc.description.abstractThe neurodevelopmental disorder Pitt Hopkins syndrome (PTHS) causes clinical symptoms similar to Rett syndrome (RTT) patients. However, RTT is caused by MECP2 mutations whereas mutations in the TCF4 gene lead to PTHS. The mechanistic commonalities underling these two disorders are unknown, but their shared symptomology suggest that convergent pathway-level disruption likely exists. We reprogrammed patient skin derived fibroblasts into induced neuronal progenitor cells. Interestingly, we discovered that MeCP2 levels were decreased in PTHS patient iNPCs relative to healthy controls and that both iNPCs and iAstrocytes displayed defects in function and differentiation in a mutation-specific manner. When Tcf4þ+/- mice were genetically crossed with mice overexpressing MeCP2, molecular and phenotypic defects were significantly ameliorated, underlining and important role of MeCP2 in PTHS pathology. Importantly, post-natal intracerebroventricular gene replacement therapy with adeno-associated viral vector serotype 9 (AAV9)-expressing MeCP2 (AAV9.P546.MeCP2) significantly improved iNPC and iAstrocyte function and effectively ameliorated histological and behavioral defects in Tcf4þ+/- mice. Combined, our data suggest a previously unknown role of MeCP2 in PTHS pathology and common pathways that might be affected in multiple neurodevelopmental disorders. Our work highlights potential novel therapeutic targets for PTHS, including upregulation of MeCP2 expression or its downstream targets or, potentially, MeCP2-based gene therapy.
dc.identifier.doi10.1016/j.neurot.2024.e00376
dc.identifier.urihttps://repositorio.ucsc.cl/handle/25022009/11943
dc.languageeng
dc.publisherElsevier
dc.rightsregistro bibliográfico
dc.subjectPitt Hopkins syndrome
dc.subjectTCF4
dc.subjectAAV gene therapy
dc.subjectMecp2
dc.titleMeCP2 gene therapy ameliorates disease phenotype in mouse model for Pitt Hopkins syndrome
dc.typeartículo
dspace.entity.typePublication
oairecerif.author.affiliationFacultad de Medicina
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