Nanoparticles that deliver triplex-forming peptide nucleic acid molecules correct F508del CFTR in airway epithelium

Nicole Ali McNeer, Kavitha Anandalingam, Rachel J. Fields, Christina Caputo, Sascha Kopic, Anisha Gupta, Elias Quijano, Lee Polikoff, Yong Kong, Raman Bahal, John P. Geibel, Peter M. Glazer, W. Mark Saltzman and Marie E. Egan ()
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Nicole Ali McNeer: Yale University
Kavitha Anandalingam: Yale University
Rachel J. Fields: Yale University
Christina Caputo: Yale School of Medicine
Sascha Kopic: Yale School of Medicine
Anisha Gupta: Yale School of Medicine
Elias Quijano: Yale University
Lee Polikoff: Yale School of Medicine
Yong Kong: Yale Department of Molecular Biophysics and Biochemistry
Raman Bahal: Yale School of Medicine
John P. Geibel: Yale School of Medicine
Peter M. Glazer: Yale School of Medicine
W. Mark Saltzman: Yale University
Marie E. Egan: Yale School of Medicine

Nature Communications, 2015, vol. 6, issue 1, 1-11

Abstract: Abstract 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.

Date: 2015
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DOI: 10.1038/ncomms7952

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