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

Hannes Steinkellner, Prakasha Kempaiah, Alexander V. Beribisky, Sandra Pferschy, Julia Etzler, Anna Huber, Victoria Sarne, Winfried Neuhaus, Mario Kuttke, Jan Bauer, Jayamuruga P. Arunachalam, John Christodoulou, Ralf Dressel, Alexander Mildner, Marco Prinz, Franco Laccone

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)972-983
Number of pages12
JournalInternational Journal of Biological Macromolecules
StatePublished - Jun 1 2022


  • Brain function
  • Broader autism phenotype
  • MeCP2
  • Protein replacement therapy
  • Rett syndrome

ASJC Scopus subject areas

  • Molecular Biology
  • Structural Biology
  • Biochemistry


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