In vivo correction of anaemia in β-thalassemic mice by γPNA-mediated gene editing with nanoparticle delivery

Raman Bahal, Nicole Ali McNeer, Elias Quijano, Yanfeng Liu, Parker Sulkowski, Audrey Turchick, Yi-Chien Lu, Dinesh C. Bhunia, Arunava Manna, Dale L. Greiner, Michael A. Brehm, Christopher J. Cheng, Francesc López-Giráldez, Adele Ricciardi, Jagadish Beloor, Diane S. Krause, Priti Kumar, Patrick G. Gallagher, Demetrios T. Braddock, W. Mark Saltzman, Danith H. Ly and Peter M. Glazer ()
Additional contact information
Raman Bahal: Yale University
Nicole Ali McNeer: Yale University
Elias Quijano: Yale University
Yanfeng Liu: Yale University
Parker Sulkowski: Yale University
Audrey Turchick: Yale University
Yi-Chien Lu: Yale University
Dinesh C. Bhunia: Carnegie Mellon University
Arunava Manna: Carnegie Mellon University
Dale L. Greiner: Program in Molecular Medicine, University of Massachusetts Medical School
Michael A. Brehm: Program in Molecular Medicine, University of Massachusetts Medical School
Christopher J. Cheng: Yale University
Francesc López-Giráldez: Yale Center for Genome Analysis (YCGA), Yale University
Adele Ricciardi: Yale University
Jagadish Beloor: Section of Infectious Disease, Yale University
Diane S. Krause: Yale University
Priti Kumar: Section of Infectious Disease, Yale University
Patrick G. Gallagher: Yale University
Demetrios T. Braddock: Yale University
W. Mark Saltzman: Yale University
Danith H. Ly: Carnegie Mellon University
Peter M. Glazer: Yale University

Nature Communications, 2016, vol. 7, issue 1, 1-14

Abstract: Abstract The blood disorder, β-thalassaemia, is considered an attractive target for gene correction. Site-specific triplex formation has been shown to induce DNA repair and thereby catalyse genome editing. Here we report that triplex-forming peptide nucleic acids (PNAs) substituted at the γ position plus stimulation of the stem cell factor (SCF)/c-Kit pathway yielded high levels of gene editing in haematopoietic stem cells (HSCs) in a mouse model of human β-thalassaemia. Injection of thalassemic mice with SCF plus nanoparticles containing γPNAs and donor DNAs ameliorated the disease phenotype, with sustained elevation of blood haemoglobin levels into the normal range, reduced reticulocytosis, reversal of splenomegaly and up to 7% β-globin gene correction in HSCs, with extremely low off-target effects. The combination of nanoparticle delivery, next generation γPNAs and SCF treatment may offer a minimally invasive treatment for genetic disorders of the blood that can be achieved safely and simply by intravenous administration.

Date: 2016
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DOI: 10.1038/ncomms13304

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