In Vivo Repair of a Protein Underlying a Neurological Disorder by Programmable RNA Editing

John R. Sinnamon, Susan Y. Kim, Jenna R. Fisk, Zhen Song, Hiroyuki Nakai, Sophia Jeng, Shannon K. McWeeney, Gail Mandel

Research output: Contribution to journalArticlepeer-review

42 Scopus citations


Programmable RNA editing is gaining momentum as an approach to repair mutations, but its efficiency in repairing endogenous mutant RNA in complex tissue is unknown. Here we apply this approach to the brain and successfully repair a guanosine-to-adenosine mutation in methyl CpG binding protein 2 RNA that causes the neurodevelopmental disease Rett syndrome. Repair is mediated by hippocampal injections of juvenile Mecp2317G>A mice with an adeno-associated virus expressing the hyperactive catalytic domain of adenosine deaminase acting on RNA 2 and Mecp2 guide. After 1 month, 50% of Mecp2 RNA is recoded in three different hippocampal neuronal populations. MeCP2 protein localization to heterochromatin is restored in neurons to 50% of wild-type levels. Whole-transcriptome RNA analysis of one neuronal population indicates that the majority of off-target editing sites exhibit rates of 30% or less. This study demonstrates that programmable RNA editing can be utilized to repair mutations in mouse models of neurological disease.

Original languageEnglish (US)
Article number107878
JournalCell Reports
Issue number2
StatePublished - Jul 14 2020


  • ADAR
  • MeCP2
  • RNA editing
  • Rett syndrome
  • adenosine deaminase acting on RNA

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology


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