Development of pegylated forms of recombinant Rhodosporidium toruloides phenylalanine ammonia-lyase for the treatment of classical phenylketonuria.

[classical phenylketonuria]

Phenylketonuria (PKU ) is a metabolic disorder due primarily to mutations in the PAH gene that impair both phenylalanine hydroxylase activity and disposal of l-phenylalanine from the normal diet . Excess phenylalanine is toxic to cognitive development and a low -phenylalanine diet prevents mental retardation , but it is a difficult therapeutic option . Previous studies with recombinant phenylalanine ammonia-lyase , PAL , demonstrated pharmacologic and physiologic proofs of principle for PAL as an alternative therapy for PKU but its immunogenicity was problematic . From a series of formulations of linear and branched polyethylene glycols chemically conjugated to PAL , we have created a parenteral therapeutic agent for PKU treatment . All the pegylated molecules were fully characterized in vitro and the most promising formulations were then tested in vivo in the PKU mouse model . The linear 20 -kDa PEG-PAL combination abolished in vivo immunogenicity after repeated challenge while retaining full catabolic activity against phenylalanine , suggesting potential as a novel PKU therapeutic .