The Children's Hospital
of Philadelphia (CHOP) and the Perelman School of Medicine at the University of
Pennsylvania have demonstrated an effective tool which can be used for prenatal
gene editing to edit out disease-causing genes in the fetus. Using mouse
models, the team used CRISPR-Cas9 and base editor 3 (BE3) gene-editing tools
the researchers reduced cholesterol levels, improved liver function and
prevented neonatal death in mice affected by a deadly mutation causing the
disease hereditary tyrosinemia type 1 (HT1).
type 1 (HT1)
is a genetic disorder leading to increased blood levels of
amino acid tyrosine which is a building block of proteins. This disorder is
caused by a deficiency of the enzyme fumarylacetoacetate hydrolase which is
essential to break down tyrosine. The enzyme deficiency is due to a genetic
mutation in the FAH gene.
The disease appears in
infancy and presents with symptoms like jaundice, vomiting, diarrhea, nosebleeds
and general weakness. HT1 can often lead to total liver and kidney failure
. Treatment with
nitisinone must be started at the earliest along with a strict diet with
restricted tyrosine and phenylalanine.
demonstrated by the research group is a precursor to the potential for
CRISPR-Cas9 guided gene editing to cure genetic disorders before birth.
According to the study co-leader William H. Peranteau, MD, pediatric and fetal
surgeon at CHOP's Center for Fetal Diagnosis and Treatment, the team hopes to
use this strategy for prenatal interventions to cure hereditary diseases which
have no treatment and potentially fatal.
Kiran Musunuru, MD, PhD,
MPH, associate professor of cardiovascular medicine at Penn and study co-leader
said that the group used base editing to turn off the disease-causing genetic
In the current study,
the researchers used base editor 3
which is safer than just using
CRISPR-Cas9. The mice which were treated with BE3 had improved liver function
and better survival rates than mice which were just administered with
To deliver BE3, the
group used adenoviruses which are proven to be effective in gene therapeutics.
The group is also looking at other delivery mechanisms like lipid nanoparticles
to avoid unintended side effects of adenoviruses.
include further investigations into base editing to move beyond genetic
diseases associated with just the liver. According to Peranteau, more time is
needed to translate this into bedside clinical applications. However, this mode
of gene editing has immense potential for life-threatening genetic disorders.
The study has been
published in Nature Medicine.
- Treatment of a metabolic liver disease by in vivo genome base editing in adult mice - (https://www.nature.com/articles/s41591-018-0209-1)
- Tyrosinemia type 1- (https://rarediseases.info.nih.gov/diseases/2658/tyrosinemia-type-1)