A modified CRISPR/Cas9 method was able to correct a sufficient number of mutated genes in mouse liver cells to normalize phenylalanine levels.
Parents of newborns may be familiar with the metabolic disorder phenylketonuria (PKU). Babies with PKU need a special diet so that the amino acid phenylalanine does not accumulate in the body. If left untreated, the children may suffer massive mental disability. There has been no cure for this disorder to date.
In a study published today in Nature Medicine, a team of researchers led by ETH professor Gerald Schwank has taken advantage of a method to correct mutated genes in liver cells and thus heal the disease. Using a modified CRISPR/Cas9 system, the researchers changed the DNA sequence of the corresponding gene in adult mice. The liver cells were then able to produce functioning Pah enzymes, and the mice were healed.
The new genome-editing tool is much more efficient than the traditional CRISPR/Cas9 method: up to 60% of all copies of the mutant gene in the mouse liver were corrected. This resulted in the concentration of phenylalanine falling to normal levels and the animals no longer showing any signs of the disorder.
Clinical studies in other animal models would have to follow in order to test the efficacy and safety of the new genome-editing tool for application in humans. However, Schwank considers the risks to be low. After applying the editing tool in the mouse model, the researchers looked for non-target mutations, but they didn’t find any.
“The human liver consists of several billion cells,” says Schwank. “In none of them we want to induce any mutations that could cause cancer.”
Testing is also needed to find out whether the adeno-associated virus used by the researchers as a vehicle for applying the gene-editing tool causes any adverse effects.
Phenylketonuria is not the only genetic metabolic disorder that affects the liver. For example, urea cycle disorders prevent the body from removing ammonia from the blood and metabolizing it to urea. This results primarily in dysfunctions of the central nervous system. The only currently available option to cure this disease is liver transplantation. Therefore, Schwank would like to test the newly developed genome-editing tool for use in such diseases as well.
Image: Based on the CRISPR-Cas method, researchers developed a tool for the targeted correction of defective genes. Image courtesy of colourbox.