TY - JOUR
T1 - Tissue-specific modulation of CRISPR activity by miRNA-sensing guide RNAs
AU - Garcia-Guerra, Antonio
AU - Sathyaprakash, Chaitra
AU - De Jong, Olivier G.
AU - Lim, Wooi F.
AU - Vader, Pieter
AU - El Andaloussi, Samir
AU - Bath, Jonathan
AU - Reine Gutierrez, Jesus
AU - Aoki, Yoshitsugu
AU - Turberfield, Andrew J.
AU - Wood, Matthew J.A.
AU - Rinaldi, Carlo
PY - 2025/1/22
Y1 - 2025/1/22
N2 - Nucleic acid nanostructures offer unique opportunities for biomedical applications due to their sequence-programmable structures and functions, which enable the design of complex responses to molecular cues. Control of the biological activity of therapeutic cargoes based on endogenous molecular signatures holds the potential to overcome major hurdles in translational research: cell specificity and off-target effects. Endogenous microRNAs (miRNAs) can be used to profile cell type and cell state, and are ideal inputs for RNA nanodevices. Here, we present CRISPR MiRAGE (miRNA-activated genome editing), a tool comprising a dynamic single-guide RNA that senses miRNA complexed with Argonaute proteins and controls downstream CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) activity based on the detected miRNA signature. We study the operation of the miRNA-sensing single-guide RNA and attain muscle-specific activation of gene editing through CRISPR MiRAGE in models of Duchenne muscular dystrophy. By enabling RNA-controlled gene editing activity, this technology creates opportunities to advance tissue-specific CRISPR treatments for human diseases.
AB - Nucleic acid nanostructures offer unique opportunities for biomedical applications due to their sequence-programmable structures and functions, which enable the design of complex responses to molecular cues. Control of the biological activity of therapeutic cargoes based on endogenous molecular signatures holds the potential to overcome major hurdles in translational research: cell specificity and off-target effects. Endogenous microRNAs (miRNAs) can be used to profile cell type and cell state, and are ideal inputs for RNA nanodevices. Here, we present CRISPR MiRAGE (miRNA-activated genome editing), a tool comprising a dynamic single-guide RNA that senses miRNA complexed with Argonaute proteins and controls downstream CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) activity based on the detected miRNA signature. We study the operation of the miRNA-sensing single-guide RNA and attain muscle-specific activation of gene editing through CRISPR MiRAGE in models of Duchenne muscular dystrophy. By enabling RNA-controlled gene editing activity, this technology creates opportunities to advance tissue-specific CRISPR treatments for human diseases.
U2 - 10.1093/nar/gkaf016
DO - 10.1093/nar/gkaf016
M3 - Article
SN - 0305-1048
VL - 53
JO - Nucleic Acids Research
JF - Nucleic Acids Research
IS - 2
M1 - gkaf016
ER -
