Evaluation of orally administered PEGylated phenylalanine ammonia lyase in mice for the treatment of Phenylketonuria.

Abstract

Phenylketonuria (PKU), a Mendelian autosomal recessive phenotype (OMIM 261600), is an inborn error of metabolism causing impaired postnatal cognitive development in the absence of treatment. We used the Pah(enu2/enu2) PKU mouse model to study oral enzyme substitution therapy with various chemically modified formulations of phenylalanine ammonia lyase (Av-p.C503S/p.C565S/p.F18A PAL). In vivo studies with the most therapeutically effective formulation (5kDa PEG-Av-p.C503S/p.C565S/p.F18A PAL) revealed that this conjugate, given orally, yielded statistically significant (p=0.0029) and therapeutically relevant reduction (~40%) in plasma phenylalanine (Phe) levels. Phe reduction occurred in a dose- and loading-dependent manner; sustained clinically and statistically significant reduction of plasma Phe levels was observed with treatment ranging between 0.3 IU and 9 IU and with more frequent and smaller dosings. Oral PAL therapy could potentially serve as an adjunct therapy, perhaps with dietary treatment, and will work independently of phenylalanine hydroxylase (PAH), correcting such forms of hyperphenylalaninemias regardless of the PAH mutations carried by the patient.

• Authors: Christineh N Sarkissian, Tse Siang Kang, Alejandra Gámez, Charles R Scriver, Raymond C Stevens
• Journal: Molecular genetics and metabolism (Mol Genet Metab) Vol. 104 Issue 3 Pg. 249-54 (Nov 2011) ISSN: 1096-7206 [Electronic] United States
• PMID: 21803624 (Publication Type: Evaluation Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Inc. All rights reserved.

Chemical References

• Alginates
• Hexuronic Acids
• Recombinant Proteins
• Phenylalanine
• Glucuronic Acid
• Chitosan
• Dextran Sulfate
• Phenylalanine Ammonia-Lyase

Topics

• Administration, Oral
• Alginates
• Anabaena variabilis (enzymology)
• Analysis of Variance
• Animals
• Basidiomycota (enzymology)
• Chitosan
• Dextran Sulfate
• Dose-Response Relationship, Drug
• Glucuronic Acid
• Hexuronic Acids
• Mice
• Nanoparticles
• Phenylalanine (blood)
• Phenylalanine Ammonia-Lyase (administration & dosage, genetics, therapeutic use)
• Phenylketonurias (drug therapy)
• Recombinant Proteins (biosynthesis, metabolism)