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Nat Commun. 2018 Jun 26;9(1):2481. doi: 10.1038/s41467-018-04894-2.

In utero nanoparticle delivery for site-specific genome editing.

Author information

1
Department of Biomedical Engineering, Yale University, New Haven, CT, 06511, USA.
2
Department of Therapeutic Radiology, Yale University, New Haven, CT, 06520, USA.
3
Department of Surgery, Yale University, New Haven, CT, 06520, USA.
4
Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT, 06269, USA.
5
Department of Genetics, Yale University, New Haven, CT, 06520, USA.
6
Yale Center for Genome Analysis (YCGA), Yale University, New Haven, CT, 06477, USA.
7
Department of Neurosurgery, Yale University, New Haven, CT, 06520, USA.
8
Department of Chemistry and Center for Nucleic Acids Science and Technology (CNAST), Carnegie Mellon University, Pittsburgh, Pennsylvania, 15213, USA.
9
Department of Surgery, Yale University, New Haven, CT, 06520, USA. david.stitelman@yale.edu.
10
Department of Therapeutic Radiology, Yale University, New Haven, CT, 06520, USA. peter.glazer@yale.edu.
11
Department of Genetics, Yale University, New Haven, CT, 06520, USA. peter.glazer@yale.edu.
12
Department of Biomedical Engineering, Yale University, New Haven, CT, 06511, USA. mark.saltzman@yale.edu.

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.

PMID:
29946143
PMCID:
PMC6018676
DOI:
10.1038/s41467-018-04894-2
[Indexed for MEDLINE]
Free PMC Article

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