title: Preclinical evaluation of multiple species of PEGylated recombinant phenylalanine ammonia lyase for the treatment of phenylketonuria.
abstract: Phenylketonuria (PKU) is a metabolic disorder, in which loss of phenylalanine hydroxylase activity results in neurotoxic levels of phenylalanine. We used the Pah(enu2/enu2) PKU mouse model in short- and long-term studies of enzyme substitution therapy with PEGylated phenylalanine ammonia lyase (PEG-PAL conjugates) from 4 different species. The most therapeutically effective PAL (Av, Anabaena variabilis) species was one without the highest specific activity, but with the highest stability; indicating the importance of protein stability in the development of effective protein therapeutics. A PEG-Av-p.C503S/p.C565S-PAL effectively lowered phenylalanine levels in both vascular space and brain tissue over a >90 day trial period, resulting in reduced manifestations associated with PKU, including reversal of PKU-associated hypopigmentation and enhanced animal health. Phenylalanine reduction occurred in a dose- and loading-dependent manner, and PEGylation reduced the neutralizing immune response to the enzyme. Human clinical trials with PEG-Av-p.C503S/p.C565S-PAL as a treatment for PKU are underway.
authors.affiliation: Department of Biology, McGill University, Montreal, QC, Canada H3A 1B1.
authors.forename: Christineh N
authors.initials: CN
authors.lastname: Sarkissian
authors.forename: Alejandra
authors.initials: A
authors.lastname: Gámez
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.forename: Marilyse
authors.initials: M
authors.lastname: Charbonneau
authors.forename: Paul
authors.initials: P
authors.lastname: Fitzpatrick
authors.forename: Jeffrey F
authors.initials: JF
authors.lastname: Lemontt
authors.forename: Bin
authors.initials: B
authors.lastname: Zhao
authors.forename: Michael
authors.initials: M
authors.lastname: Vellard
authors.forename: Sean M
authors.initials: SM
authors.lastname: Bell
authors.forename: Carroll
authors.initials: C
authors.lastname: Henschell
authors.forename: Amy
authors.initials: A
authors.lastname: Lambert
authors.forename: Laurie
authors.initials: L
authors.lastname: Tsuruda
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Stevens
authors.forename: Charles R
authors.initials: CR
authors.lastname: Scriver
mesh_terms: D046870:Anabaena variabilis / Q000201:enzymology*; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D001426:Bacterial Proteins / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004795:Enzyme Stability / Q000502:physiology; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D009928:Organ Specificity / Q000187:drug effects; D010649:Phenylalanine / Q000378:metabolism; D010650:Phenylalanine Ammonia-Lyase / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D010661:Phenylketonurias / Q000188:drug therapy* / Q000378:metabolism; D011092:Polyethylene Glycols; D011994:Recombinant Proteins / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D001426:Bacterial Proteins; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D010649:Phenylalanine; D010650:Phenylalanine Ammonia-Lyase