Recent advances towards gene therapy for propionic acidemia: translation to the clinic

Introduction: Propionic acidemia (PA) is a metabolic genetic disease that occurs in 1 in 100,000 live births in United States and up to 1 in 3,000 in certain populations. PA is caused by deficiency in either the α or β subunits of the mitochondrial enzyme propionyl CoA carboxylase (PCC), encoded by the PCCA and PCCB genes. This disease causes metabolic acidosis, ketosis, vomiting, lethargy, cognitive reductions, and death. There is no cure for PA. Areas covered: This review discusses the genetics and biology of PA in humans. The development of mouse models of the disease is discussed. The use of gene therapy as a replacement for elective liver transplantation is proposed. The strategies, challenges, and preclinical results of gene therapy are detailed in the review. Expert opinion: Gene therapy for propionic acidemia in humans is feasible. Regardless of the payload, gene, mRNA, or genome editing approaches will stand or fall based on their ability to hit the right tissue targets. Therapies that target only the liver will be an improvement to elective liver transplantation, but will neglect repairing damage in at-risk tissues like the brain and the heart.