WASHINGTON: In a first, scientists have performed prenatal
geneediting to prevent a
lethal metabolic disorder in animals, offering the potential to
treat human congenital diseases
beforebirth.
Using both CRISPR-Cas9 and base editor 3 (BE3)
gene-
editing tools, researchers from University of Pennsylvania and Children's Hospital of
Philadelphia (CHOP) in the US reduced
cholesterol levels in healthy mice treated in utero by targeting a
gene that regulates those levels.
They also used prenatal
geneediting 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 diagnosed early in pregnancy," said William H Peranteau, a pediatric and foetal 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," said Peranteau.
"We used base
editing to turn off the effects of a
disease-causing genetic mutation," said Kiran Musunuru, an associate professor at University of Pennsylvania.
"We also plan to use the same base-
editing technique not just to disrupt a mutation's effects, but to directly correct the mutation," said Musunuru.
In the study, scientists used base editor 3 (BE3), which takes clustered regularly interspersed short palindromic repeats (CRISPR), joins it with a modified CRISPR-associated protein 9 to form a partially active version of the CRISPR-Cas 9 tool, and harnesses it as a homing device to carry an
enzyme to a highly specific genetic location in the liver cells of foetal mice.
The enzyme chemically modified the targeted genetic sequence, changing one type of
DNA base to another.
After
birth, the mice in the study carried stable amounts of edited liver cells for up to three months after the prenatal treatment, with no evidence of unwanted, off-target
editing at other DNA sites.
"A significant amount of work needs to be done
before prenatal
geneediting can be translated to the clinic, including investigations into more clinically relevant delivery mechanisms and ensuring the safety of this approach," Peranteau said.