Site-directed RNA repair of endogenous Mecp2 RNA in neurons

著者: John R. Sinnamon, Susan Y. Kim, Glen M. Corson, Zhen Song, Hiroyuki Nakai, John P. Adelman, Gail Mandel - Proceedings of the National Academy of Sciences, PNAS 2017 被引用: 109

Significance Rett syndrome (RTT) is a neurological disease caused by mutations in the gene encoding the global transcriptional regulator, Methyl CpG Binding Protein 2 (MECP2). We exploit a strategy to repair mutant Mecp2 mRNA that if successful should reverse symptoms. The strategy utilizes the catalytic activity of a naturally occurring enzyme, Adenosine Deaminase Acting on RNA (ADAR2), which in brain alters the mRNA sequence and function of proteins. In cultured RTT neurons co-expressing a modified ADAR2 protein and an appropriate RNA guide, a human mutation in Mecp2 mRNA is repaired efficiently. RNA repair restores MeCP2 function, consistent with reversal of the pathological consequences of the RTT mutation. Our strategy holds promise for new therapeutic approaches to RTT and other neurological diseases.