TY - JOUR
T1 - TAT-MeCP2 protein variants rescue disease phenotypes in human and mouse models of Rett syndrome
AU - Steinkellner, Hannes
AU - Kempaiah, Prakasha
AU - Beribisky, Alexander V.
AU - Pferschy, Sandra
AU - Etzler, Julia
AU - Huber, Anna
AU - Sarne, Victoria
AU - Neuhaus, Winfried
AU - Kuttke, Mario
AU - Bauer, Jan
AU - Arunachalam, Jayamuruga P.
AU - Christodoulou, John
AU - Dressel, Ralf
AU - Mildner, Alexander
AU - Prinz, Marco
AU - Laccone, Franco
N1 - Publisher Copyright:
© 2022
PY - 2022/6/1
Y1 - 2022/6/1
N2 - 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.
AB - 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.
KW - Brain function
KW - Broader autism phenotype
KW - MeCP2
KW - Protein replacement therapy
KW - Rett syndrome
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UR - http://www.scopus.com/inward/citedby.url?scp=85129138420&partnerID=8YFLogxK
U2 - 10.1016/j.ijbiomac.2022.04.080
DO - 10.1016/j.ijbiomac.2022.04.080
M3 - Article
C2 - 35460749
AN - SCOPUS:85129138420
SN - 0141-8130
VL - 209
SP - 972
EP - 983
JO - International Journal of Biological Macromolecules
JF - International Journal of Biological Macromolecules
ER -