GSE96065
In vivo delivery of CRISPR/Cas9 nanocomplexes in post-mitotic neurons for Alzheimer's disease therapy
The clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 system has emerged as a powerful technique for correcting genetic disease-causing mutations. However, in vivo gene editing using CRISPR/Cas9 remains a major challenge currently limiting its therapeutic application for disease correction. In the present study, we developed novel Cas9/gRNA nanocomplexes that lead to efficient in vivo gene targeting of neurons in the brain. We demonstrate the in vivo efficacy of Cas9-nanocomplexes as therapeutic agents for Alzheimer's disease (AD) by targeting the BACE1 gene. Remarkably, in vivo BACE1 targeting by using Cas9-nanocomplexes results in decreased Aß42 production and improvement of cognitive decline in an AD mouse model. These results suggest that Cas9-nanocomplexes represent an effective in vivo gene editing platform in the brain, and that this strategy may be applicable to the treatment of a broad range of neurological diseases. Overall design: HEK 293T cell was used for human control and CRISPR/Cas9 nanocomplex (Nano) treated samples. Mouse brain was used for control and CRISPR/Cas9 nanocomplex (Nano) treated samples. For human samples, PCR amplicons of 4 target sites were pooled and sequenced (total 2 samples). For mouse samples, PCR amplicons of 4 target sites were sequenced separately (total 8 samples).