Phenylketonuria (PKU) is one of the most common inborn errors of metabolism. PKU, commonly detected in infants during newborn screening, is due to recessively-inherited phenylalanine hydroxylase (PAH) deficiency. Current treatment strategies rely on restriction of dietary phenylalanine (Phe) intake to prevent the major manifestations of the disease, however, dietary therapy is complicated, unpalatable, and must be sustained throughout life to prevent neurocognitive disability associated with chronic hyperphenylalaninemia. Here, we propose to generate a large animal swine model of PKU to evaluate novel treatments strategies that are difficult to evaluate in murine PKU models due to their small size and physiological and anatomical differences. These novel therapies, including enzyme substitution therapy, hepatocyte transplantation, and gene therapy (liver- directed and muscle-directed gene therapy strategies employing both recombinant adeno-associated virus (rAAV) and non-viral naked DNA vector systems), could be applied to both PKU and many other inherited genetic diseases. A large animal model to evaluate the safety and efficacy of these therapies is critical to bridge the gap between laboratory experiments and the treatment of patients in the clinic. Additionally, a swine model of PKU is critical to understanding the molecular mechanisms through which hyperphenylalaninemia causes harm to the brain and results in physical, neurological and behavioral deficits seen in patients. Further, a model in which physical and molecular phenotypes can be evaluated during Phe-restricted diet treatment, following discontinuation of Phe-restricted diet, and during the implementation of novel treatments such as gene therapy will be critical for better treating patients with PKU. The preclinical experiments we propose to conduct will be vital to understanding the limiting issues in treating patients and will have direct influence upon the design of future human clinical trials
This SBIR aims to develop a swine model of Phenylketonuria (PKU), a commonly inherited genetic disease affecting 1 in 16,500 children born in the US. Left untreated, PKU is associated with growth failure, acquired microcephaly, hypopigmentation, and severe developmental disability. While dietary phenylalanine restriction prevent the major manifestations of the disease, this dietary restriction is complicated, unpalatable, and must be sustained throughout life. The physical, behavioral, and neurological symptoms that PKU patients often experience are poorly understood and several academic and industry researchers are seeking new treatment modalities to treat PKU. Several successful gene- or cell-therapies have been developed in mice that have yet to enter clinical trials in patients due to the immense size differential having impact on therapeutic delivery and dosage parameters. Pigs are comparable in size and anatomy to humans enabling optimization of treatment modalities prior to clinical trials. Further, lessons learned from a PKU pig model would be directly applicable to the development of novel treatments for related inborn errors of metabolism.