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

Cell Rep. 2020 Jul 14;32(2):107878. doi: 10.1016/j.celrep.2020.107878.


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.

Keywords: ADAR; MeCP2; RNA editing; Rett syndrome; adenosine deaminase acting on RNA.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Cell Line
  • Gene Expression Profiling
  • Genetic Therapy*
  • HEK293 Cells
  • Heterochromatin / metabolism
  • Hippocampus / metabolism
  • Humans
  • Male
  • Methyl-CpG-Binding Protein 2 / chemistry
  • Methyl-CpG-Binding Protein 2 / genetics*
  • Mice
  • Nervous System Diseases / genetics*
  • Nervous System Diseases / therapy*
  • RNA / genetics
  • RNA Editing / genetics*
  • Stereotaxic Techniques


  • Heterochromatin
  • Methyl-CpG-Binding Protein 2
  • RNA