Penn scientists correct genetic flaw in mice fetuses, expanding in utero CRISPR reach to lung diseases

Remember when researchers applied CRISPR to edit genes of mice fetuses while they are still in the womb, sparing them from death by liver disease? The same team from the University of Pennsylvania has now tested the same idea — albeit with a different technique — in genetic lung diseases.

In the burgeoning world of gene editing spawned by CRISPR, in utero treatment can be seen as a midpoint between early embryo editing (which passes the genetic alterations to future generations) and editing after birth, which can be too late for patients with certain lethal diseases.

William Peranteau

It is one of these conditions that study co-leaders Edward Morrisey and William Peranteau set out to thwart in their latest proof-of-concept study, published in Science Translational Medicine this week. Specifically, they look at a gene tied to surfactants, a crucial lipoprotein that reduces lung surface tension and enables normal lung function. An SFTPC mutation in humans, as in mice, means newborns are almost certain to die within hours of birth — and that’s what happened with all of the mice in the experiment that were born with the mutation.

The team, however, managed to inactivate the mutant gene in some of the fetuses, allowing 7 (out of 87 treated with CRISPR) to survive beyond 24 hours, including 5 that seemed to remain healthy for seven days.

To specifically deliver the gene editing reagent to the lungs, the scientists injected it in amniotic fluid so that with every inhalation, CRISPR would get straight to the epithelial cells lining the airways. The injection took place four days before birth, the equivalent of humans’ third trimester.

They note that this method resulted in “relatively uniform targeting of most of the major pulmonary epithelial cell types,” a potential advantage over postnatal inhalations that tend to cause differential distribution.

“Given that many congenital lung diseases such as cystic fibrosis and inherited [surfactant protein] disease are generally caused by monogenic mutations, they should be ideal candidates for gene editing technologies,” the study authors write.

Edward Morrisey

Like any mouse study, of course, the results are merely signs that researchers could proceed with caution. And the researchers add that prenatal gene editing can expose the mother to risks — something they wouldn’t have to worry about in postnatal editing. But the researchers are clearly stoked about the potential here.

“The ability to cure or mitigate a disease via gene editing in mid to late gestation before birth and the onset of irreversible pathology is very exciting,” Peranteau said in a statement. “This is particularly true for diseases that affect the lungs, whose function becomes dramatically more important at the time of birth.”

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