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Preclinical Evaluation of Multiple Species of PEGylated Recombinant Phenylalanine Ammonia Lyase for the Treatment of Phenylketonuria

Christineh N. Sarkissian, Alejandra Gámez, Lin Wang, Marilyse Charbonneau, Paul Fitzpatrick, Jeffrey F. Lemontt, Bin Zhao, Michael Vellard, Sean M. Bell, Carroll Henschell, Amy Lambert, Laurie Tsuruda, Raymond C. Stevens and Charles R. Scriver
Proceedings of the National Academy of Sciences of the United States of America
Vol. 105, No. 52 (Dec. 30, 2008), pp. 20894-20899
Stable URL: http://www.jstor.org/stable/25465004
Page Count: 6
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Since scans are not currently available to screen readers, please contact JSTOR User Support for access. We'll provide a PDF copy for your screen reader.
Preclinical Evaluation of Multiple Species of PEGylated Recombinant Phenylalanine Ammonia Lyase for the Treatment of Phenylketonuria
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Abstract

Phenylketonuria (PKU) is a metabolic disorder, in which loss of phenylalanine hydroxylase activity results in neurotoxic levels of phenylalanine. We used the $Pah^{enu2/enu2}$ PKU mouse model in short- and long-term studies of enzyme substitution therapy with PEGylated phenylalanine ammonia lyase (PEG-PAL conjugates) from 4 different species. The most therapeutically effective PAL (Av, Anabaena variabilis) species was one without the highest specific activity, but with the highest stability; indicating the importance of protein stability in the development of effective protein therapeutics. A PEG-Av-p.C503S/p.C565S-PAL effectively lowered phenylalanine levels in both vascular space and brain tissue over a >90 day trial period, resulting in reduced manifestations associated with PKU, including reversal of PKU-associated hypopigmentation and enhanced animal health. Phenylalanine reduction occurred in a dose- and loading-dependent manner, and PEGylation reduced the neutralizing immune response to the enzyme. Human clinical trials with PEG-Av-p.C503S/p.C565S-PAL as a treatment for PKU are underway.

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