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MeCP2 gene therapy ameliorates disease phenotype in mouse model for Pitt Hopkins syndrome
Dennys, Cassandra
Vermudez, Sheryl
Deacon, Robert
Sierra-Delgado, J.
Rich, Kelly
Zhang, Xiaojin
Buch, Aditi
Weiss, Kelly
Moxley, Yuta
Rajpal, Hemangi
Espinoza, Francisca
Powers, Samantha
Gogliotti, Rocco
Cogram, Patricia
Niswender, Colleen
Meyer, Kathrin
Elsevier
2024
The 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.
Pitt Hopkins syndrome
TCF4
AAV gene therapy
Mecp2