Journal
NATURE COMMUNICATIONS
Volume 6, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms7952
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Funding
- NIGMS Medical Scientist Training Program [T32GM07205]
- Hartwell Foundation
- National Institute of Health [R01HL082655, R01AI112443, R01EB000487]
- National Heart, Lung, and Blood institute [F30HL110372]
- National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH) [TL 1 RR024137]
- NIH Roadmap for Medical Research
- Yale Pediatric Basic Science Training Program from the National Child Health and Human Development Institute [T32HD068201]
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Cystic fibrosis (CF) is a lethal genetic disorder most commonly caused by the F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. It is not readily amenable to gene therapy because of its systemic nature and challenges including in vivo gene delivery and transient gene expression. Here we use triplex-forming peptide nucleic acids and donor DNA in biodegradable polymer nanoparticles to correct F508del. We confirm modification with sequencing and a functional chloride efflux assay. In vitro correction of chloride efflux occurs in up to 25% of human cells. Deep-sequencing reveals negligible off-target effects in partially homologous sites. Intranasal delivery of nanoparticles in CF mice produces changes in the nasal epithelium potential difference assay, consistent with corrected CFTR function. Also, gene correction is detected in the nasal and lung tissue. This work represents facile genome engineering in vivo with oligonucleotides using a nanoparticle system to achieve clinically relevant levels of gene editing without off-target effects.
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