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Nat Commun. 2016 Oct 26;7:13304. doi: 10.1038/ncomms13304.

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

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Department of Therapeutic Radiology, Yale University, New Haven, Connecticut 06520, USA.
Department of Biomedical Engineering, Yale University, New Haven, Connecticut 06511, USA.
Department of Genetics, Yale University, New Haven, Connecticut 06520, USA.
Department of Laboratory Medicine, Yale University, New Haven, Connecticut 06520, USA.
Department of Chemistry and Center for Nucleic Acids Science and Technology (CNAST), Carnegie Mellon University, Pittsburgh, Pennsylvania 15213, USA.
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
Yale Center for Genome Analysis (YCGA), Yale University, Orange, Connecticut 06477, USA.
Department of Internal Medicine, Section of Infectious Disease, Yale University, New Haven, Connecticut 06520, USA.
Department of Pediatrics, Yale University, New Haven, Connecticut 06520, USA.
Department of Pathology, Yale University, New Haven, Connecticut 06520, USA.


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.

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