title: Erythrocytes encapsulated with phenylalanine hydroxylase exhibit improved pharmacokinetics and lowered plasma phenylalanine levels in normal mice.
abstract: Enzyme replacement therapy is often hampered by the rapid clearance and degradation of the administered enzyme, limiting its efficacy and requiring frequent dosing. Encapsulation of therapeutic molecules into red blood cells (RBCs) is a clinically proven approach to improve the pharmacokinetics and efficacy of biologics and small molecule drugs. Here we evaluated the ability of RBCs encapsulated with phenylalanine hydroxylase (PAH) to metabolize phenylalanine (Phe) from the blood and confer sustained enzymatic activity in the circulation. Significant quantities of PAH were successfully encapsulated within murine RBCs (PAH-RBCs) with minimal loss of endogenous hemoglobin. While intravenously administered free PAH enzyme was rapidly eliminated from the blood within a few hours, PAH-RBCs persisted in the circulation for at least 10days. A single injection of PAH-RBCs was able to decrease Phe levels by nearly 80% in normal mice. These results demonstrate the ability of enzyme-loaded RBCs to metabolize circulating amino acids and highlight the potential to treat disorders of amino acid metabolism.
authors.affiliation: Genzyme, a Sanofi Company, 49 New York Avenue, Framingham, MA 01701-9322, USA. nelson.yew@genzyme.com
authors.forename: Nelson S
authors.initials: NS
authors.lastname: Yew
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Dufour
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Przybylska
authors.forename: Julie
authors.initials: J
authors.lastname: Putelat
authors.forename: Cristin
authors.initials: C
authors.lastname: Crawley
authors.forename: Meta
authors.initials: M
authors.lastname: Foster
authors.forename: Sarah
authors.initials: S
authors.lastname: Gentry
authors.forename: David
authors.initials: D
authors.lastname: Reczek
authors.forename: Alla
authors.initials: A
authors.lastname: Kloss
authors.forename: Aurélien
authors.initials: A
authors.lastname: Meyzaud
authors.forename: Françoise
authors.initials: F
authors.lastname: Horand
authors.forename: Seng H
authors.initials: SH
authors.lastname: Cheng
authors.forename: Yann
authors.initials: Y
authors.lastname: Godfrin
mesh_terms: D000818:Animals; D016503:Drug Delivery Systems; D056947:Enzyme Replacement Therapy; D004912:Erythrocytes / Q000201:enzymology*; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D010649:Phenylalanine / Q000097:blood*; D010651:Phenylalanine Hydroxylase / Q000235:genetics* / Q000493:pharmacokinetics; D010661:Phenylketonurias / Q000097:blood / Q000201:enzymology* / Q000235:genetics / Q000628:therapy
chemical_list: D006454:Hemoglobins; D010649:Phenylalanine; D010651:Phenylalanine Hydroxylase
keywords: Drug delivery; Enzyme therapy; Erythrocytes; Pharmacokinetics; Phenylalanine; Phenylketonuria