Prenatal gene editing treats disease before birth

FOR the first time, scientists have performed prenatal gene editing to prevent a lethal metabolic disorder in laboratory animals, offering the potential to treat human congenital diseases before birth.

Published Tuesday in Nature Medicine, research from Children's Hospital of Philadelphia (CHOP) and the Perelman School of Medicine at the University of Pennsylvania, United States (U.S.), offers proof-of-concept for prenatal use of a sophisticated, low-toxicity tool that efficiently edits DNA building blocks in disease-causing genes.

Using both CRISPR-CAS9 and base editor 3 (BE3) gene-editing tools, the team reduced cholesterol levels in healthy mice treated in utero by targeting a gene that regulates those levels. They also used prenatal gene editing to improve liver function and prevent neonatal death in a subgroup of mice that had been engineered with a mutation causing the lethal liver disease hereditary tyrosinemia type 1 (HT1).

HT1 in humans usually appears during infancy, and it is often treatable with a medicine called nitisinone and a strict diet. However, when treatments fail, patients are at risk of liver failure or liver cancer. Prenatal treatment could open a door to disease prevention, for HT1 and potentially for other congenital disorders.

"Our ultimate goal is to translate the approach used in these proof-of-concept studies to treat severe diseases diag- nosed early in pregnancy," said study co-leader William H. Peranteau, MD, a pediatric and fetal surgeon in CHOP'S Center for Fetal Diagnosis and Treatment. "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."

"We used base editing to turn off the effects of a disease-causing genetic mutation," said study co-leader Kiran Musunuru, MD, PHD, MPH, an associate professor of Cardiovascular Medicine at Penn. "We also plan to use the same base-editing technique not just to disrupt a mutation's effects, but to directly correct the mutation."