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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • DNA / administration & dosage
  • DNA / genetics
  • Disease Models, Animal
  • Gene Editing / methods*
  • Genetic Therapy / methods*
  • Hematopoietic Stem Cells / metabolism*
  • Hemoglobins / analysis
  • Humans
  • Injections, Intravenous
  • Mice
  • Mice, Transgenic
  • Nanoparticles / administration & dosage
  • Peptide Nucleic Acids / administration & dosage
  • Peptide Nucleic Acids / genetics*
  • Proto-Oncogene Proteins c-kit / metabolism
  • Stem Cell Factor / administration & dosage
  • Stem Cell Factor / metabolism
  • beta-Globins / genetics
  • beta-Thalassemia / blood
  • beta-Thalassemia / genetics
  • beta-Thalassemia / therapy*


  • Hemoglobins
  • Peptide Nucleic Acids
  • Stem Cell Factor
  • beta-Globins
  • DNA
  • Proto-Oncogene Proteins c-kit