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Advanced genetic therapies for the treatment of Rett syndrome: state of the art and future perspectives

Loss and gain of functions mutations in the X-linked MECP2 (methyl-CpG-binding protein 2) gene are responsible for a set of generally severe neurological disorders that can affect both genders. In particular, Mecp2 deficiency is mainly associated with Rett syndrome (RTT) in girls, while duplication...

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Autores principales: Palmieri, Michela, Pozzer, Diego, Landsberger, Nicoletta
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10248472/
https://www.ncbi.nlm.nih.gov/pubmed/37304036
http://dx.doi.org/10.3389/fnins.2023.1172805
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author Palmieri, Michela
Pozzer, Diego
Landsberger, Nicoletta
author_facet Palmieri, Michela
Pozzer, Diego
Landsberger, Nicoletta
author_sort Palmieri, Michela
collection PubMed
description Loss and gain of functions mutations in the X-linked MECP2 (methyl-CpG-binding protein 2) gene are responsible for a set of generally severe neurological disorders that can affect both genders. In particular, Mecp2 deficiency is mainly associated with Rett syndrome (RTT) in girls, while duplication of the MECP2 gene leads, mainly in boys, to the MECP2 duplication syndrome (MDS). No cure is currently available for MECP2 related disorders. However, several studies have reported that by re-expressing the wild-type gene is possible to restore defective phenotypes of Mecp2 null animals. This proof of principle endorsed many laboratories to search for novel therapeutic strategies to cure RTT. Besides pharmacological approaches aimed at modulating MeCP2-downstream pathways, genetic targeting of MECP2 or its transcript have been largely proposed. Remarkably, two studies focused on augmentative gene therapy were recently approved for clinical trials. Both use molecular strategies to well-control gene dosage. Notably, the recent development of genome editing technologies has opened an alternative way to specifically target MECP2 without altering its physiological levels. Other attractive approaches exclusively applicable for nonsense mutations are the translational read-through (TR) and t-RNA suppressor therapy. Reactivation of the MECP2 locus on the silent X chromosome represents another valid choice for the disease. In this article, we intend to review the most recent genetic interventions for the treatment of RTT, describing the current state of the art, and the related advantages and concerns. We will also discuss the possible application of other advanced therapies, based on molecular delivery through nanoparticles, already proposed for other neurological disorders but still not tested in RTT.
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spelling pubmed-102484722023-06-09 Advanced genetic therapies for the treatment of Rett syndrome: state of the art and future perspectives Palmieri, Michela Pozzer, Diego Landsberger, Nicoletta Front Neurosci Neuroscience Loss and gain of functions mutations in the X-linked MECP2 (methyl-CpG-binding protein 2) gene are responsible for a set of generally severe neurological disorders that can affect both genders. In particular, Mecp2 deficiency is mainly associated with Rett syndrome (RTT) in girls, while duplication of the MECP2 gene leads, mainly in boys, to the MECP2 duplication syndrome (MDS). No cure is currently available for MECP2 related disorders. However, several studies have reported that by re-expressing the wild-type gene is possible to restore defective phenotypes of Mecp2 null animals. This proof of principle endorsed many laboratories to search for novel therapeutic strategies to cure RTT. Besides pharmacological approaches aimed at modulating MeCP2-downstream pathways, genetic targeting of MECP2 or its transcript have been largely proposed. Remarkably, two studies focused on augmentative gene therapy were recently approved for clinical trials. Both use molecular strategies to well-control gene dosage. Notably, the recent development of genome editing technologies has opened an alternative way to specifically target MECP2 without altering its physiological levels. Other attractive approaches exclusively applicable for nonsense mutations are the translational read-through (TR) and t-RNA suppressor therapy. Reactivation of the MECP2 locus on the silent X chromosome represents another valid choice for the disease. In this article, we intend to review the most recent genetic interventions for the treatment of RTT, describing the current state of the art, and the related advantages and concerns. We will also discuss the possible application of other advanced therapies, based on molecular delivery through nanoparticles, already proposed for other neurological disorders but still not tested in RTT. Frontiers Media S.A. 2023-05-25 /pmc/articles/PMC10248472/ /pubmed/37304036 http://dx.doi.org/10.3389/fnins.2023.1172805 Text en Copyright © 2023 Palmieri, Pozzer and Landsberger. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neuroscience
Palmieri, Michela
Pozzer, Diego
Landsberger, Nicoletta
Advanced genetic therapies for the treatment of Rett syndrome: state of the art and future perspectives
title Advanced genetic therapies for the treatment of Rett syndrome: state of the art and future perspectives
title_full Advanced genetic therapies for the treatment of Rett syndrome: state of the art and future perspectives
title_fullStr Advanced genetic therapies for the treatment of Rett syndrome: state of the art and future perspectives
title_full_unstemmed Advanced genetic therapies for the treatment of Rett syndrome: state of the art and future perspectives
title_short Advanced genetic therapies for the treatment of Rett syndrome: state of the art and future perspectives
title_sort advanced genetic therapies for the treatment of rett syndrome: state of the art and future perspectives
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10248472/
https://www.ncbi.nlm.nih.gov/pubmed/37304036
http://dx.doi.org/10.3389/fnins.2023.1172805
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