@article{33c56a2ed5674448a6a3feea0de050f4,
title = "In Vivo Repair of a Protein Underlying a Neurological Disorder by Programmable RNA Editing",
abstract = "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",
author = "Sinnamon, {John R.} and Kim, {Susan Y.} and Fisk, {Jenna R.} and Zhen Song and Hiroyuki Nakai and Sophia Jeng and McWeeney, {Shannon K.} and Gail Mandel",
note = "Funding Information: We thank Christine Schmidt-Weber and Justine Nguyen for mouse husbandry, Joshua Rosenthal (Marine Biological Laboratories, MA) for help and advice when applying the editase system to Rett syndrome, and James M. Wilson (University of Pennsylvania) for the p5E18-VD2/9 plasmid. Discussions and encouragement from people in the laboratories of Adrian Bird (Wellcome Trust Centre for Cell Biology, University of Edinburgh), Michael E. Greenberg (Harvard Medical School), and Paul Brehm (Vollum Institute, Oregon Health and Science University) are greatly appreciated. An NIH Director's Transformative Research award (NS087726) to G.M. Joshua Rosenthal, Paul Brehm and John Adelman, NIH R01 NS088399 (to H.N.), and grants from the Rett Syndrome Research Trust (to G.M. and J.R.S.) funded this work. J.R.S. and G.M. designed the research. J.R.S. S.Y.K. J.R.F. and Z.S. performed the research. H.N. provided AAV advice, virus, and analytic tools. S.J. and S.K.M. performed the bioinformatics analysis with suggestions from J.R.S. J.R.S. S.Y.K. S.J. S.K.M. and G.M. analyzed the data. J.R.S. and G.M. wrote the paper, which was edited by all authors. G.M. is a scientific co-founder of Vico Therapeutics. She holds equity but is not an employee, and her laboratory receives no Vico funding. G.M. and J.R.S. are co-inventors on provisional patent application PCT/US18/55029 filed by Oregon Health and Science University. Funding Information: We thank Christine Schmidt-Weber and Justine Nguyen for mouse husbandry, Joshua Rosenthal (Marine Biological Laboratories, MA) for help and advice when applying the editase system to Rett syndrome, and James M. Wilson (University of Pennsylvania) for the p5E18-VD2/9 plasmid. Discussions and encouragement from people in the laboratories of Adrian Bird (Wellcome Trust Centre for Cell Biology, University of Edinburgh), Michael E. Greenberg (Harvard Medical School), and Paul Brehm (Vollum Institute, Oregon Health and Science University) are greatly appreciated. An NIH Director{\textquoteright}s Transformative Research award ( NS087726) to G.M., Joshua Rosenthal, Paul Brehm and John Adelman, NIH R01 NS088399 (to H.N.), and grants from the Rett Syndrome Research Trust (to G.M. and J.R.S.) funded this work. Publisher Copyright: {\textcopyright} 2020 The Author(s)",
year = "2020",
month = jul,
day = "14",
doi = "10.1016/j.celrep.2020.107878",
language = "English (US)",
volume = "32",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "2",
}