Journal
JOURNAL OF NANOBIOTECHNOLOGY
Volume 17, Issue -, Pages -Publisher
BMC
DOI: 10.1186/s12951-019-0452-8
Keywords
CRISPR-Cas system; Nanoliposome; Type 2 diabetes mellitus; Dipeptidyl peptidase-4 gene
Funding
- GRRC program of Gyeonggi province (Photonics-Medical Convergence Technology Research Center) [GRRC 2016B02]
- Ajou University
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BackgroundProtein-based Cas9 in vivo gene editing therapeutics have practical limitations owing to their instability and low efficacy. To overcome these obstacles and improve stability, we designed a nanocarrier primarily consisting of lecithin that can efficiently target liver disease and encapsulate complexes of Cas9 with a single-stranded guide RNA (sgRNA) ribonucleoprotein (Cas9-RNP) through polymer fusion self-assembly.ResultsIn this study, we optimized an sgRNA sequence specifically for dipeptidyl peptidase-4 gene (DPP-4) to modulate the function of glucagon-like peptide 1. We then injected our nanocarrier Cas9-RNP complexes directly into type 2 diabetes mellitus (T2DM) db/db mice, which disrupted the expression of DPP-4 gene in T2DM mice with remarkable efficacy. The decline in DPP-4 enzyme activity was also accompanied by normalized blood glucose levels, insulin response, and reduced liver and kidney damage. These outcomes were found to be similar to those of sitagliptin, the current chemical DPP-4 inhibition therapy drug which requires recurrent doses.ConclusionsOur results demonstrate that a nano-liposomal carrier system with therapeutic Cas9-RNP has great potential as a platform to improve genomic editing therapies for human liver diseases.
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