Genome editing treats inherited liver disease PKU in mice

Researchers have successfully used genome editing in mice to correct a genetic mutation that causes the liver disease phenylketonuria (PKU).

PKU is a genetic disease where the liver enzyme phenylalanine hydroxylase (Pah) that breaks down the amino acid phenylalanine is not produced at sufficient levels. As a result, phenylalanine accumulates and disrupts motor and cognitive development, and can lead to profound mental disability. To avoid this, people with PKU have to stick to a strict diet excluding phenylalanine. At present, there is no cure for the condition at present. 

In a study published in Nature Medicine, researchers used CRISPR/Cas9 coupled with an enzyme called cytidine deaminase, which base-edited the disease-causing genetic variant to the healthy version. 

'This approach has great potential for application in humans,' said Professor Gerald Schwank of ETH Zurich, an author of the study. 

Using a viral vector injected into the bloodstream of adult mice, the genome editing technique corrected the mutation in up to 60 percent of cells in the liver. This boosted levels of the Pah enzyme to healthy levels in the mice. Previous genome editing techniques led to successful edits in only a tiny minority of mice liver cells. 

'Here we've achieved several fold higher editing rates – nobody has managed that so far,' said Professor Schwank. 

The researchers did not detect any off-target genetic alterations. However, Professor Schwank intends to do further studies to ensure that the method introduces no unwanted alterations. 

'The human liver consists of several billion cells. In none of them we want to induce any mutations that could cause cancer,' Professor Schwank said. 

This proof-of-concept study paves the way for research in other mammals. Professor Schwank next hopes to carry out studies in pigs, before moving to human trials if the animal model work is successful.