Gene editing cures anemia in fetal mice

Researchers have used gene editing within mouse fetuses in utero to cure thalassemia, a severe form of anemia, a Yale-led study reports. Humans with thalassemia have low levels of hemoglobin, resulting in fatigue and weakness and, in the worst cases, necessitating lifetimes of blood transfusions and bone-marrow transplants.

Thalassemia stems from mutations in the genes that encode hemoglobin’s component proteins, called globins. In the study, published June 26 in Nature Communications, the researchers injected specially designed nanoparticles into mouse fetuses to correct an engineered mutation in a gene that acts on globin.

Specifically, the researchers introduced nanoparticles containing both the correct globin DNA sequences and also peptide nucleic acids (PNAs), which mimic DNA, into thalassemic mouse fetuses in utero. When the nanoparticles entered target cells, the PNAs bound to the mutated DNA and stimulated DNA repair pathways, which used the introduced DNA sequences to correct the mutated globin genes.

Mice that received in utero nanoparticle injections had normal lifespans and hemoglobin levels. Mice in the control group, which did not receive the treatment, had lower hemoglobin levels, abnormal red blood cells, and reduced survival.

This groundbreaking work, the first report of gene editing within a fetus, was a collaboration among three Yale laboratories, and represents the PhD thesis project of Adele Ricciardi, an MD/PhD student.

Peter M. Glazer, MD, PhD, chair and Robert E. Hunter Professor of Therapeutic Radiology and professor of genetics, devised the technique of using PNAs and DNAs for gene editing. W. Mark Saltzman, PhD, Goizueta Foundation Professor of Biomedical Engineering, and professor of cellular and molecular physiology and of chemical engineering, engineered the nanoparticles for safe delivery of PNA/DNA. David H. Stitelman, MD, assistant professor of pediatric surgery, and of obstetrics, gynecology, and reproductive sciences, provided expertise on in utero intervention and fetal gene therapies.

Prenatal genetic testing can now detect genetic disorders in utero. This study suggests that, one day, doctors could cure such diseases prior to birth. “We believe this opens the door to thinking about life-prolonging treatments for fetuses during pregnancy, that involve only a single injection in utero,” says Saltzman, who notes that the fragility of a fetus demands as few interventions as possible.