{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T08:18:14Z","timestamp":1790065094414,"version":"4.0.1"},"reference-count":36,"publisher":"National Academy of Sciences","issue":"52","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2008,12,30]]},"abstract":"<jats:p>\n                    Phenylketonuria (PKU) is a metabolic disorder, in which loss of phenylalanine hydroxylase activity results in neurotoxic levels of phenylalanine. We used the\n                    <jats:italic>\n                      Pah\n                      <jats:sup>enu2\/enu2<\/jats:sup>\n                    <\/jats:italic>\n                    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 (\n                    <jats:italic>Av, Anabaena variabilis<\/jats:italic>\n                    ) 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-\n                    <jats:italic>Av<\/jats:italic>\n                    -p.C503S\/p.C565S-PAL effectively lowered phenylalanine levels in both vascular space and brain tissue over a &gt;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-\n                    <jats:italic>Av<\/jats:italic>\n                    -p.C503S\/p.C565S-PAL as a treatment for PKU are underway.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0808421105","type":"journal-article","created":{"date-parts":[[2008,12,18]],"date-time":"2008-12-18T20:56:27Z","timestamp":1229633787000},"page":"20894-20899","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":98,"title":["Preclinical evaluation of multiple species of PEGylated recombinant phenylalanine ammonia lyase for the treatment of phenylketonuria"],"prefix":"10.1073","volume":"105","author":[{"given":"Christineh N.","family":"Sarkissian","sequence":"first","affiliation":[{"name":"Departments of Biology, Human Genetics, and Pediatrics, McGill University, Montreal, QC, Canada H3A 1B1;"},{"name":"Debelle Laboratory, McGill University-Montreal Children's Hospital Research Institute, 2300 Tupper Street, A-717, Montreal, QC, Canada H3H 1P3;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alejandra","family":"G\u00e1mez","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marilyse","family":"Charbonneau","sequence":"additional","affiliation":[{"name":"Debelle Laboratory, McGill University-Montreal Children's Hospital Research Institute, 2300 Tupper Street, A-717, Montreal, QC, Canada H3H 1P3;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Fitzpatrick","sequence":"additional","affiliation":[{"name":"BioMarin Pharmaceutical, Inc., 105 Digital Drive, Novato, CA 94949"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey F.","family":"Lemontt","sequence":"additional","affiliation":[{"name":"BioMarin Pharmaceutical, Inc., 105 Digital Drive, Novato, CA 94949"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Zhao","sequence":"additional","affiliation":[{"name":"BioMarin Pharmaceutical, Inc., 105 Digital Drive, Novato, CA 94949"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Vellard","sequence":"additional","affiliation":[{"name":"BioMarin Pharmaceutical, Inc., 105 Digital Drive, Novato, CA 94949"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sean M.","family":"Bell","sequence":"additional","affiliation":[{"name":"BioMarin Pharmaceutical, Inc., 105 Digital Drive, Novato, CA 94949"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carroll","family":"Henschell","sequence":"additional","affiliation":[{"name":"BioMarin Pharmaceutical, Inc., 105 Digital Drive, Novato, CA 94949"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy","family":"Lambert","sequence":"additional","affiliation":[{"name":"BioMarin Pharmaceutical, Inc., 105 Digital Drive, Novato, CA 94949"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurie","family":"Tsuruda","sequence":"additional","affiliation":[{"name":"BioMarin Pharmaceutical, Inc., 105 Digital Drive, Novato, CA 94949"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raymond C.","family":"Stevens","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037; 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