PT  - JOURNAL ARTICLE
AU  - Sinnamon, John R
AU  - Kim, Susan Y
AU  - Fisk, Jenna R
AU  - Song, Zhen
AU  - Nakai, Hiroyuki
AU  - Jeng, Sophia
AU  - McWeeney, Shannon K
AU  - Mandel, Gail
TI  - In vivo repair of a protein underlying a neurological disorder by programmable RNA editing
AID  - 10.1101/2020.02.26.966820
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.02.26.966820
4099  - http://biorxiv.org/content/early/2020/02/27/2020.02.26.966820.short
4100  - http://biorxiv.org/content/early/2020/02/27/2020.02.26.966820.full
AB  - RNA base editing is gaining momentum as an approach to repair mutations, but its application to neurological disease has not been established. We have succeeded in directed transcript editing of a pathological mutation in a mouse model of the neurodevelopmental disease, Rett syndrome. Specifically, we directed editing of a guanosine to adenosine mutation in RNA encoding Methyl CpG Binding Protein 2 (MECP2). Repair was mediated by injecting the hippocampus of juvenile Rett mice with an adeno-associated virus expressing both an engineered enzyme containing the catalytic domain of Adenosine Deaminase Acting on RNA 2 and a Mecp2 targeting guide. After one month, 50% of Mecp2 RNA was recoded in three different hippocampal neuronal subtypes, and the ability of MeCP2 protein to associate with heterochromatin was similarly restored to 50% of wild-type levels. This study represents the first in vivo programmable RNA editing applied to a model of neurological disease.