In utero nanoparticle delivery for site-specific genome editing

Adele S. Ricciardi, Raman Bahal, James S. Farrelly, Elias Quijano, Anthony H. Bianchi, Valerie L. Luks, Rachael Putman, Francesc López-Giráldez, Süleyman Coşkun, Eric Song, Yanfeng Liu, Wei-Che Hsieh, Danith H. Ly, David H. Stitelman (), Peter M. Glazer () and W. Mark Saltzman ()
Additional contact information
Adele S. Ricciardi: Yale University
Raman Bahal: Yale University
James S. Farrelly: Yale University
Elias Quijano: Yale University
Anthony H. Bianchi: Yale University
Valerie L. Luks: Yale University
Rachael Putman: Yale University
Francesc López-Giráldez: Yale University
Süleyman Coşkun: Yale University
Eric Song: Yale University
Yanfeng Liu: Yale University
Wei-Che Hsieh: Carnegie Mellon University
Danith H. Ly: Carnegie Mellon University
David H. Stitelman: Yale University
Peter M. Glazer: Yale University
W. Mark Saltzman: Yale University

Nature Communications, 2018, vol. 9, issue 1, 1-11

Abstract: Abstract Genetic diseases can be diagnosed early during pregnancy, but many monogenic disorders continue to cause considerable neonatal and pediatric morbidity and mortality. Early intervention through intrauterine gene editing, however, could correct the genetic defect, potentially allowing for normal organ development, functional disease improvement, or cure. Here we demonstrate safe intravenous and intra-amniotic administration of polymeric nanoparticles to fetal mouse tissues at selected gestational ages with no effect on survival or postnatal growth. In utero introduction of nanoparticles containing peptide nucleic acids (PNAs) and donor DNAs corrects a disease-causing mutation in the β-globin gene in a mouse model of human β-thalassemia, yielding sustained postnatal elevation of blood hemoglobin levels into the normal range, reduced reticulocyte counts, reversal of splenomegaly, and improved survival, with no detected off-target mutations in partially homologous loci. This work may provide the basis for a safe and versatile method of fetal gene editing for human monogenic disorders.

Date: 2018
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DOI: 10.1038/s41467-018-04894-2

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