- CRISPR-Cas9 has been hailed as the gene editing tool of choice to correct genetic disorders
- For the first time, scientists have used CRISPR-Cas9 guided gene editing to prevent genetic disorders before birth
- An effective tool was used for prenatal gene editing to edit out disease-causing genes in the fetus
- CRISPR-Cas9 and base editor 3 (BE3) gene-editing tools were used to reduce cholesterol levels, improve liver function and prevent neonatal death
CRISPR-Cas9 has been
hailed as the gene editing tool of choice to correct genetic disorders. For the
first time, scientists have used CRISPR-Cas9 guided gene editing to prevent
genetic disorders before birth.
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).
Hereditary tyrosinemia 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.
Treatment with nitisinone must be started at the earliest along with a strict diet with restricted tyrosine and phenylalanine.
The proof-of-concept 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 mutation.
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 nitisinone.
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.
Future directions 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)