Prospects for Cell-Directed Curative Therapy of Phenylketonuria (PKU)

Abstract

Phenylketonuria (PKU) due to recessively inherited phenylalanine hydroxylase (PAH) deficiency is among the most common inborn errors of metabolism. Dietary therapy begun early in infancy prevents the major manifestations of the disease but shortcomings to treatment continue to exist including lifelong commitment to a complicated and unpalatable diet, poor adherence to diet in adolescence and adulthood, and consequently a range of unsatisfactory outcomes, including neuropsychiatric disorders, frequently develop. Novel treatments that do not strictly depend upon dietary protein restriction are actively sought. This review discusses the potential for and the limitations of permanently curative cell-directed treatment of PKU, including liver-directed gene therapy and gene editing, if initiated during early infancy. A fictional but realistic vignette of a family with a new baby girl recently diagnosed with PKU is presented. What is needed to permanently cure her?