Fetal against fatal: In utero genome editing to prevent metabolic disease

In utero CRISPR editing allows early intervention for inborn errors of metabolism in mice. The discovery of CRISPR-mediated genome editing has led to lots of excitement in the eld of inborn errors of metabolism (IEMs). Individual IEMs are often rare, but as a group they are a large cause of disability and mortality in children. It is estimated that more than 1000 IEMs exist, primarily caused by monogenic mutations leading to the buildup of toxic metabolic intermediates. The opportunity to prevent such misery by correcting the defective gene or preventing the toxic accumulation has paved the way for new therapeutic avenues, especially when the intervention can be applied early in life. Rossidis and colleagues developed a CRISPR-mediated strategy for in utero genome editing. By injecting specic editing constructs in the vitelline vein of mice, they showed that the fetus could be effectively targeted, especially in the liver and the heart. As their proof of concept, they disrupted the function of Pcsk9, a gene whose loss-of-function lowers cholesterol levels. When Pcsk9 was edited in utero to express a premature stop codon, the mice postnatally showed lower circulating PCSK9 protein levels and serum cholesterol. To make a stronger therapeutic case, the authors moved to a mouse model for the IEM tyrosinemia type 1. This disease is caused by mutations in the Fah1 gene that codes for an enzyme involved in tyrosine breakdown. Its deciency leads to liver and kidney failure when untreated, but disease progression can be slowed-but not stopped-by inhibition of the upstream enzyme HPD with the drug nitisinone. Introducing a nonsense mutation in the Hpd1 gene through the in utero delivery method rescued the lethality of the Fah-decient mice and improved their liver function, at least to the same extent as nitisinone. Although these results are the rst stepping stones to therapy in humans, the route to human application is still long and full of ethical questions. Moreover, it remains to be seen whether HPD editing is a viable therapy in humans, as HPD mutations were described as the cause for tyrosinemia type 3. Nonetheless, the strategy opens doors to cure the long list of IEMs that currently have no treatment options available.