Transcriptional activation with Cas9 activator nanocomplexes rescues Alzheimer's disease pathology

CRISPR/Cas9-mediated gene activation is a potential therapeutic strategy that does not induce double-strand break (DSB) DNA damage. However, in vivo gene activation via a Cas9 activator remains a challenge, currently limiting its therapeutic applications. We developed a Cas9 activator nanocomplex th...

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Bibliographic Details
Published in:Biomaterials 2021-12, Vol.279, p.121229-121229, Article 121229
Main Authors: Park, Hanseul, Hwang, Yerim, Kim, Jongpil
Format: Article
Language:English
Subjects:
Adam10
Alzheimer Disease - drug therapy
Alzheimer Disease - genetics
Alzheimer's disease
Animals
Cas9 activator nanocomplex
CRISPR-Cas Systems
DNA Breaks, Double-Stranded
Genetic Therapy
In vivo gene Activating
Mice
Transcriptional Activation
α-Secretase
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Summary:CRISPR/Cas9-mediated gene activation is a potential therapeutic strategy that does not induce double-strand break (DSB) DNA damage. However, in vivo gene activation via a Cas9 activator remains a challenge, currently limiting its therapeutic applications. We developed a Cas9 activator nanocomplex that efficiently activates an endogenous gene in the brain in vivo, suggesting its possible application in novel therapeutics. We demonstrated a potential treatment application of the Cas9 activator nanocomplex by activating Adam10 in the mouse brain without introducing insertions and deletions (inDels). Remarkably, in vivo activation of Adam10 with the Cas9 activator nanocomplex improved cognitive deficits in an Alzheimer's disease (AD) mouse model. These results demonstrate the therapeutic potential of Cas9 activator nanocomplexes for a wide range of neurological diseases.
ISSN:0142-9612
1878-5905
DOI:10.1016/j.biomaterials.2021.121229