Phenylketonuria Research Today is a free monthly online journal that collates and summarizes the latest research about Phenylketonuria, including details on genetics, causes, symptoms, hereditary disorder.

Converting an injectable protein therapeutic into an oral form: phenylalanine ammonia lyase for phenylketonuria.

Kang TS, Wang L, Sarkissian CN, Gámez A, Scriver CR, Stevens RC

Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, GAC 1200, La Jolla, CA 92037, USA.

Phenylalanine ammonia lyase (PAL) has long been recognized as a potential enzyme replacement therapeutic for treatment of phenylketonuria. However, various strategies for the oral delivery of PAL have been complicated by the low intestinal pH, aggressive proteolytic digestion and circulation time in the GI tract. In this work, we report 3 strategies to address these challenges. First, we used site-directed mutagenesis of a chymotrypsin cleavage site to modestly improve protease resistance; second, we used silica sol-gel material as a matrix to demonstrate that a silica matrix can provide protection to entrapped PAL proteins against intestinal proteases, as well as a low pH of 3.5; finally, we demonstrated that PEGylation of AvPAL surface lysines can reduce the inactivation of the enzyme by trypsin.

Published 16 December 2009 in Mol Genet Metab, 99(1): 4-9.
Full-text of this article is available online (may require subscription).

© 2005-2010 Phenylketonuria Research Today. All Rights Reserved.