title: Erythrocyte-mediated delivery of phenylalanine ammonia lyase for the treatment of phenylketonuria in BTBR-Pah(enu2) mice.
abstract: Phenylketonuria (PKU) is an autosomal recessive genetic disease caused by defects in the phenylalanine hydroxylase gene. Preclinical and clinical investigations suggest that phenylalanine ammonia lyase (PAL) could be an effective alternative for the treatment of PKU. The aim of this study is to investigate if erythrocytes loaded with PAL may act as a safe delivery system able to overcome bioavailability issues and to provide, in vivo, a therapeutically relevant concentration of enzyme. Murine erythrocytes were loaded with recombinant PAL from Anabaena variabilis (rAvPAL) and their ability to perform as bioreactors was assessed in vivo in adult BTBR-Pah(enu2) mice, the genetic murine model of PKU. Three groups of mice were treated with a single i.v. injection of rAvPAL-RBCs at three different doses to select the most appropriate one for assessment of efficacy. Repeated administrations at 9-10 day-intervals of the selected dose for 10 weeks showed that the therapeutic effect was persistent and not affected by the generation of antibodies induced by the recombinant enzyme. This therapeutic approach deserves further in vivo evaluation either as a potential option for the treatment of PKU patients or as a possible model for the substitutive enzymatic treatment of other inherited metabolic disorders.
authors.affiliation: Department of Biomolecular Sciences, University of Urbino "Carlo Bo" via Saffi 2, 61029 Urbino (PU), Italy; EryDel SpA, via Sasso 36, 61029 Urbino (PU), Italy.
authors.forename: Luigia
authors.initials: L
authors.lastname: Rossi
authors.affiliation: Department of Biomolecular Sciences, University of Urbino "Carlo Bo" via Saffi 2, 61029 Urbino (PU), Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Pierigè
authors.affiliation: Department of Experimental Medicine, Sapienza University, viale del Policlinico 155, 00161 Rome, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Carducci
authors.affiliation: Department of Biomolecular Sciences, University of Urbino "Carlo Bo" via Saffi 2, 61029 Urbino (PU), Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Gabucci
authors.affiliation: Department of Psychology and Centro "Daniel Bovet", Sapienza University, via dei Marsi 78, 00185 Rome, Italy; Fondazione Santa Lucia, IRCCS, via Ardeatina 306, 00142 Rome, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Pascucci
authors.affiliation: Department of Earth, Life and Environmental Sciences, University of Urbino "Carlo Bo", Campus Scientifico Enrico Mattei-via Cà Le Suore 2/4, 61029 Urbino (PU), Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Canonico
authors.affiliation: BioMarin Pharmaceutical, Inc., 105 Digital Drive, Novato, CA 94949, USA.
authors.forename: Sean M
authors.initials: SM
authors.lastname: Bell
authors.affiliation: BioMarin Pharmaceutical, Inc., 105 Digital Drive, Novato, CA 94949, USA.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Fitzpatrick
authors.affiliation: Department of Pediatrics and Child Neurology and Psychiatry, Sapienza University, via dei Sabelli 108, 00185 Rome, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Leuzzi
authors.affiliation: Department of Biomolecular Sciences, University of Urbino "Carlo Bo" via Saffi 2, 61029 Urbino (PU), Italy; EryDel SpA, via Sasso 36, 61029 Urbino (PU), Italy. Electronic address: mauro.magnani@uniurb.it.
authors.forename: Mauro
authors.initials: M
authors.lastname: Magnani
mesh_terms: D000818:Animals; D001682:Biological Availability; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers; D016503:Drug Delivery Systems; D056947:Enzyme Replacement Therapy / Q000379:methods*; D004912:Erythrocytes / Q000378:metabolism*; D006801:Humans; D007074:Immunoglobulin G / Q000032:analysis; D051379:Mice; D008815:Mice, Inbred Strains; D010649:Phenylalanine / Q000378:metabolism; D010650:Phenylalanine Ammonia-Lyase / Q000008:administration & dosage / Q000627:therapeutic use*; D010661:Phenylketonurias / Q000188:drug therapy* / Q000235:genetics; D011994:Recombinant Proteins / Q000627:therapeutic use
chemical_list: D004337:Drug Carriers; D007074:Immunoglobulin G; D011994:Recombinant Proteins; D010649:Phenylalanine; D010650:Phenylalanine Ammonia-Lyase
keywords: Carrier erythrocytes; Drug delivery; Enzyme replacement therapy; PKU mouse model