Researchers have developed a pioneering, specific, personalized gene therapy for a newborn with a rare and life-threatening urea cycle metabolism disorder. This has been reported in the New England Journal of Medicine. Right after birth, genetic analysis identified two truncating CPS1 gene variants in the boy as the cause of his condition. Then, in just six months, researchers at the Children’s Hospital in Philadelphia successfully designed a highly targeted gene-editing approach to fix the gene defect in the boy’s liver cells. Before treating the patient, they tested the approach in the lab and in animals, and then received special FDA permission to use it on the child.

CPS1 encodes an enzyme that is located in the mitochondrial matrix of liver cells and epithelial cells in the intestinal mucosa and controls the conversion of ammonia into carbamoyl phosphate. Deficiency of carbamoyl phosphate synthetase I (CPS1) leads to toxic accumulation of ammonia in blood, which can cause severe brain damage or even death.

For their gene therapeutic approach, the researchers used the so called base editing technique. This is a modified form of the CRISPR/Cas system allowing to precisely rewrite a single DNA base at a specific site in the genome, without cutting the DNA double strand. The base editing complex to rewrite one of the two disease-causing compound heterozygous variants (p.Q335X) was administered intravenously and transported to the liver using lipid nanoparticles. Unlike viral vectors, they can be given more than once. After two administrations, early clinical results showed that the boy can now tolerate more protein in his diet and his ammonia-lowering medication has been reduced. However, a liver biopsy has not yet been performed to confirm the results directly in the tissue.