{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T15:36:43Z","timestamp":1788017803851,"version":"build-2784847793"},"reference-count":32,"publisher":"Oxford University Press (OUP)","license":[{"start":{"date-parts":[[2025,1,1]],"date-time":"2025-01-01T00:00:00Z","timestamp":1735689600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,1,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Pompe disease is a tissue glycogen disorder caused by genetic insufficiency of the GAA enzyme. GAA enzyme replacement therapies for Pompe disease have been limited by poor lysosomal trafficking of the recombinant GAA molecule through the native mannose-6-phosphate-mediated pathway. Here, we describe the successful rational engineering of a chimeric GAA enzyme that utilizes the binding affinity of a modified IGF-II moiety to its native receptor to bypass the mannose-6-phosphate-mediated lysosomal trafficking pathway, conferring a significant increase in cellular uptake of the GAA enzyme. We also demonstrate the ablation of binding between our modified IGF-II tag and two off-target receptors: IGF-I receptor and insulin receptor, as well as preserved enzymatic activity of the chimeric GAA molecule.<\/jats:p>","DOI":"10.1093\/protein\/gzaf001","type":"journal-article","created":{"date-parts":[[2025,1,23]],"date-time":"2025-01-23T15:22:21Z","timestamp":1737645741000},"source":"Crossref","is-referenced-by-count":3,"title":["Engineering of a lysosomal-targeted GAA enzyme"],"prefix":"10.1093","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-6450-8220","authenticated-orcid":false,"given":"Nicholas","family":"Marze","sequence":"first","affiliation":[{"name":"Pfizer Research and Development, Biomedicine Design , 610 Main Street, Cambridge, MA 02139 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilya","family":"Tikh","sequence":"additional","affiliation":[{"name":"Pfizer Research and Development, Biomedicine Design , 610 Main Street, Cambridge, MA 02139 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan","family":"Benard","sequence":"additional","affiliation":[{"name":"Pfizer Research and Development, Biomedicine Design , 610 Main Street, Cambridge, MA 02139 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxing","family":"Cheng","sequence":"additional","affiliation":[{"name":"Pfizer Research and Development, Biomedicine Design , 610 Main Street, Cambridge, MA 02139 ,","place":["United States"]},{"name":"Johnson & Johnson Innovative Medicine , 301 Bonney Street, Cambridge, MA 02140 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent","family":"Yu","sequence":"additional","affiliation":[{"name":"Pfizer Research and Development, Biomedicine Design , 610 Main Street, Cambridge, MA 02139 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Waijiao","family":"Cai","sequence":"additional","affiliation":[{"name":"Pfizer Research and Development, Vaccine Research and Development , 401 North Middletown Road, Pearl River, NY 10965 ,","place":["United States"]},{"name":"Pfizer Rare Disease Research Unit , 610 Main Street, Cambridge, MA 02139 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward","family":"Lavallie","sequence":"additional","affiliation":[{"name":"Pfizer Research and Development, Biomedicine Design , 610 Main Street, Cambridge, MA 02139 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erin","family":"Lopez","sequence":"additional","affiliation":[{"name":"Pfizer Rare Disease Research Unit , 610 Main Street, Cambridge, MA 02139 ,","place":["United States"]},{"name":"Chroma Medicine , 201 Brookline Ave, Boston, MA 02215 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Wang","sequence":"additional","affiliation":[{"name":"Pfizer Research and Development, Biomedicine Design , 610 Main Street, Cambridge, MA 02139 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatyana","family":"Zamkovaya","sequence":"additional","affiliation":[{"name":"Pfizer Research and Development, Biomedicine Design , 610 Main Street, Cambridge, MA 02139 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suryanarayan","family":"Somanathan","sequence":"additional","affiliation":[{"name":"Pfizer Rare Disease Research Unit , 610 Main Street, Cambridge, MA 02139 ,","place":["United States"]},{"name":"Gingko Bioworks , 27 Drydock Avenue 8th Floor, Boston, MA 02210 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,1,23]]},"reference":[{"key":"2025070100312360400_ref1","doi-asserted-by":"publisher","first-page":"e2300038","DOI":"10.1002\/biot.202300038","article-title":"The impact of expression vector position on transgene transcription allows for rational expression vector Design in a Targeted Integration System","volume":"18","author":"Beal","year":"2023","journal-title":"Biotechnol. 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