title: Development of pegylated forms of recombinant Rhodosporidium toruloides phenylalanine ammonia-lyase for the treatment of classical phenylketonuria.
abstract: 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.
authors.affiliation: Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Alejandra
authors.initials: A
authors.lastname: Gámez
authors.forename: Christineh N
authors.initials: CN
authors.lastname: Sarkissian
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.forename: Woomi
authors.initials: W
authors.lastname: Kim
authors.forename: Mary
authors.initials: M
authors.lastname: Straub
authors.forename: Marianne G
authors.initials: MG
authors.lastname: Patch
authors.forename: Lin
authors.initials: L
authors.lastname: Chen
authors.forename: Steve
authors.initials: S
authors.lastname: Striepeke
authors.forename: Paul
authors.initials: P
authors.lastname: Fitzpatrick
authors.forename: Jeffrey F
authors.initials: JF
authors.lastname: Lemontt
authors.forename: Charles
authors.initials: C
authors.lastname: O'Neill
authors.forename: Charles R
authors.initials: CR
authors.lastname: Scriver
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Stevens
mesh_terms: D000818:Animals; D000906:Antibodies / Q000097:blood; D006801:Humans; D051379:Mice; D010650:Phenylalanine Ammonia-Lyase / Q000737:chemistry / Q000276:immunology* / Q000627:therapeutic use*; D010661:Phenylketonurias / Q000188:drug therapy*; D011092:Polyethylene Glycols / Q000737:chemistry / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000737:chemistry / Q000276:immunology* / Q000627:therapeutic use*
chemical_list: D000906:Antibodies; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D010650:Phenylalanine Ammonia-Lyase