In a remarkable proof-of-concept study, scientists from the University of Pennsylvania and the Children's Hospital of Philadelphia have, for the first time, successfully used CRISPR gene-editing technology on mice in utero, to prevent the animals being born with a lethal metabolic disorder.

The ground-breaking study focused on mice engineered to have hereditary tyrosinemia type 1 (HT1), a lethal liver disease that is known to appear in humans. The research utilized a newer type of CRISPR gene-editing referred to as base editing.

Instead of chopping out unwanted strands of DNA and inserting new genes, this new technique can simply alter a base letter in a specific gene, essentially repairing a singular genetic mutation that causes disease without the possible unwanted broader side effects of completely cutting the DNA.

"We used base editing to turn off the effects of a disease-causing genetic mutation," says study co-leader Kiran Musunuru. "We also plan to use the same base-editing technique not just to disrupt a mutation's effects, but to directly correct the mutation."

In this particular experiment the fetus was not treated while it was in the womb. In order to ensure accurate delivery of the gene editor into the liver, the fetus was carefully removed from the pregnant mouse and re-implanted into the mother's uterus after treatment.

The results were incredibly positive, with the gene-edited mice all born safely displaying no evidence of off-target DNA effects. The gene editing successfully improved liver function and extended the animal's lifespan. Compared to HT1 engineered mice administered with the traditional drug treatment for the condition, the gene-edited mice displayed greatly improved general health.

"Our ultimate goal is to translate the approach used in these proof-of-concept studies to treat severe diseases diagnosed early in pregnancy," explains study co-leader William H. Peranteau. "We hope to broaden this strategy to intervene prenatally in congenital diseases that currently have no effective treatment for most patients, and result in death or severe complications in infants."

Needless to say, any human clinical application for this kind of procedure is a long way off. Apart from the enormous ethical and regulatory hurdles that would currently stifle prenatal gene editing in humans, the specific technology needs a great deal more study and refinement. However, this singular breakthrough is a major step forward in finding a cure for a large number of genetic disorders. This kind of prenatal base editing could effectively target a number of monogenetic disorders caused by single errors or mutations in just one gene.

"A significant amount of work needs to be done before prenatal gene editing can be translated to the clinic, including investigations into more clinically relevant delivery mechanisms and ensuring the safety of this approach," says Peranteau. "Nonetheless, we are excited about the potential of this approach to treat genetic diseases of the liver and other organs for which few therapeutic options exist."

The new study was published in the journal Nature Medicine.