Minimally Invasive Gene Editing Cured Thalassemia in Mice Interview with:

Peter M. Glazer, MD, PhD Robert E. Hunter Professor of Therapeutic Radiology and Professor of Genetics; Chair, Department of Therapeutic Radiology Yale University

Dr. Peter M. Glazer

Peter M. Glazer, MD, PhD
Robert E. Hunter Professor of Therapeutic Radiology and Professor of Genetics; Chair, Department of Therapeutic Radiology
Yale University What is the background for this study? What are the main findings?

Response: It is generally recognized that gene editing in blood stem cells could provide a strategy for treatment of inherited disorders such as sickle cell disease and thalassaemia. Recent excitement has focused on CRISPR/Cas9 technology because of it is so easy to use. However, the CRISPR approach introduces an active DNA cutting enzyme into cells, which can lead to off-target cuts in the genome. As an alternative, we have pursued triplex-forming peptide nucleic acids (PNAs) designed to bind site-specifically to genomic DNA via strand invasion and formation of PNA/DNA/PNA triplexes. PNAs consist of a charge-neutral peptide-like backbone and nucleobases enabling hybridization with DNA with high affinity. PNA/DNA/PNA triplexes recruit the cell’s own DNA repair machinery to initiate site-specific editing of the genome when single-stranded ‘donor DNAs’ are co-delivered as templates containing the desired sequence modification.

We found that triplex-forming PNAs substituted at the gamma position yielded high levels of gene editing in blood stem cells in a mouse model of human β-thalassaemia. Injection of thalassemic mice with nanoparticles containing gamma PNAs and donor DNAs ameliorated the disease phenotype, with sustained elevation of blood hemoglobin levels into the normal range and up to 7% β-globin gene correction in stem cells, with extremely low off-target effects. We conclude that the combination of nanoparticle delivery and next generation PNAs may offer a minimally invasive treatment for genetic disorders of the blood that can be achieved safely and simply by intravenous administration. What should readers take away from your report?

Response: This is the key take home: although other gene editing approaches have been widely used in research studies for correcting mutations, their application has been largely limited to cells and not living animals. We show in vivo PNA-mediated editing of a β-globin mutation leading to sustained normalization of blood hemoglobin levels β-thalassemic mice by a simple IV injection. What recommendations do you have for future research as a result of this study?

Response: We are continuing to improve the PNAs and nanoparticles to make them even more efficient and as safe as possible. We also are applying this technology to mouse models of sickle cell disease and cystic fibrosis. Thank you for your contribution to the community.


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, Peter M. Glazer. In vivo correction of anaemia in β-thalassemic mice by γPNA-mediated gene editing with nanoparticle delivery. Nature Communications, 2016; 7: 13304 DOI: 10.1038/NCOMMS13304

Note: Content is Not intended as medical advice. Please consult your health care provider regarding your specific medical condition and questions.

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Last Updated on October 27, 2016 by Marie Benz MD FAAD