TAT-MeCP2 protein variants rescue disease phenotypes in human and mouse models of Rett syndrome

Rett syndrome (RTT) is a neurodevelopmental disorder caused by pathogenic variants leading to functional impairment of the MeCP2 protein. Here, we used purified recombinant MeCP2e1 and MeCP2e2 protein variants fused to a TAT protein transduction domain (PTD) to evaluate their transduction ability in...

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Bibliographic Details
Published in:International journal of biological macromolecules 2022-06, Vol.209 (Pt A), p.972-983
Main Authors: Steinkellner, Hannes, Kempaiah, Prakasha, Beribisky, Alexander V., Pferschy, Sandra, Etzler, Julia, Huber, Anna, Sarne, Victoria, Neuhaus, Winfried, Kuttke, Mario, Bauer, Jan, Arunachalam, Jayamuruga P., Christodoulou, John, Dressel, Ralf, Mildner, Alexander, Prinz, Marco, Laccone, Franco
Format: Article
Language:English
Subjects:
Animals
Brain function
Broader autism phenotype
Disease Models, Animal
Gene Products, tat - genetics
Gene Products, tat - therapeutic use
Humans
MeCP2
Methyl-CpG-Binding Protein 2 - genetics
Methyl-CpG-Binding Protein 2 - metabolism
Mice
Mutation
Phenotype
Protein replacement therapy
Rett syndrome
Rett Syndrome - drug therapy
Rett Syndrome - genetics
Rett Syndrome - metabolism
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Summary:Rett syndrome (RTT) is a neurodevelopmental disorder caused by pathogenic variants leading to functional impairment of the MeCP2 protein. Here, we used purified recombinant MeCP2e1 and MeCP2e2 protein variants fused to a TAT protein transduction domain (PTD) to evaluate their transduction ability into RTT patient-derived fibroblasts and the ability to carry out their cellular function. We then assessed their transduction ability and therapeutic effects in a RTT mouse model. In vitro, TAT-MeCP2e2-eGFP reversed the pathological hyperacetylation of histones H3K9 and H4K16, a hallmark of abolition of MeCP2 function. In vivo, intraperitoneal administration of TAT-MeCP2e1 and TAT-MeCP2e2 extended the lifespan of Mecp2−/y mice by >50%. This was accompanied by rescue of hippocampal CA2 neuron size in animals treated with TAT-MeCP2e1. Taken together, these findings provide a strong indication that recombinant TAT-MeCP2 can reach mouse brains following peripheral injection and can ameliorate the phenotype of RTT mouse models. Thus, our study serves as a first step in the development of a potentially novel RTT therapy. [Display omitted]
ISSN:0141-8130
1879-0003
DOI:10.1016/j.ijbiomac.2022.04.080