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: Luigia Rossi, Francesca Pierigè, Claudia Carducci, Claudia Gabucci, Tiziana Pascucci, Barbara Canonico, Sean M Bell, Paul A Fitzpatrick, Vincenzo Leuzzi, Mauro Magnani
• Journal: Journal of controlled release : official journal of the Controlled Release Society (J Control Release) Vol. 194 Pg. 37-44 (Nov 28 2014) ISSN: 1873-4995 [Electronic] Netherlands
• PMID: 25151978 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014. Published by Elsevier B.V.

Chemical References

• Drug Carriers
• Immunoglobulin G
• Recombinant Proteins
• Phenylalanine
• Phenylalanine Ammonia-Lyase

Topics

• Animals
• Biological Availability
• Dose-Response Relationship, Drug
• Drug Carriers
• Drug Delivery Systems
• Enzyme Replacement Therapy (methods)
• Erythrocytes (metabolism)
• Humans
• Immunoglobulin G (analysis)
• Mice
• Mice, Inbred Strains
• Phenylalanine (metabolism)
• Phenylalanine Ammonia-Lyase (administration & dosage, therapeutic use)
• Phenylketonurias (drug therapy, genetics)
• Recombinant Proteins (therapeutic use)