{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T01:44:23Z","timestamp":1773279863304,"version":"3.50.1"},"reference-count":23,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2019,2,22]],"date-time":"2019-02-22T00:00:00Z","timestamp":1550793600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000071","name":"National Institute of Child Health and Human Development","doi-asserted-by":"publisher","award":["HD000912\u201038"],"award-info":[{"award-number":["HD000912\u201038"]}],"id":[{"id":"10.13039\/100000071","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Inher Metab Disea"],"published-print":{"date-parts":[[2019,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Glycogen storage disease type\u2010Ia (GSD\u2010Ia), caused by a deficiency in glucose\u20106\u2010phosphatase\u2010\u03b1 (G6Pase\u2010\u03b1 or G6PC), is characterized by impaired glucose homeostasis with a hallmark hypoglycemia, following a short fast. We have shown that <jats:italic>G6pc<\/jats:italic>\u2010deficient (<jats:italic>G6pc<\/jats:italic>\u2212\/\u2212) mice treated with recombinant adeno\u2010associated virus (rAAV) vectors expressing either wild\u2010type (WT) (rAAV\u2010hG6PC\u2010WT) or codon\u2010optimized (co) (rAAV\u2010co\u2010hG6PC) human (h) G6Pase\u2010\u03b1 maintain glucose homeostasis if they restore \u22653% of normal hepatic G6Pase\u2010\u03b1 activity. The co vector, which has a higher potency, is currently being used in a phase I\/II clinical trial for human GSD\u2010Ia (NCT 03517085). While routinely used in clinical therapies, co vectors may not always be optimal. Codon\u2010optimization can impact RNA secondary structure, change RNA\/DNA protein\u2010binding sites, affect protein conformation and function, and alter posttranscriptional modifications that may reduce potency or efficacy. We therefore sought to develop alternative approaches to increase the potency of the <jats:italic>G6PC<\/jats:italic> gene transfer vectors. Using an evolutionary sequence analysis, we identified a Ser\u2010298 to Cys\u2010298 substitution naturally found in canine, mouse, rat, and several primate G6Pase\u2010\u03b1 isozymes, that when incorporated into the WT hG6Pase\u2010\u03b1 sequence, markedly enhanced enzymatic activity. Using <jats:italic>G6pc<\/jats:italic>\u2212\/\u2212 mice, we show that the efficacy of the rAAV\u2010hG6PC\u2010S298C vector was 3\u2010fold higher than that of the rAAV\u2010hG6PC\u2010WT vector. The rAAV\u2010hG6PC\u2010S298C vector with increased efficacy, that minimizes the potential problems associated with codon\u2010optimization, offers a valuable vector for clinical translation in human GSD\u2010Ia.<\/jats:p>","DOI":"10.1002\/jimd.12069","type":"journal-article","created":{"date-parts":[[2019,2,4]],"date-time":"2019-02-04T03:19:50Z","timestamp":1549250390000},"page":"470-479","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["An evolutionary approach to optimizing glucose\u20106\u2010phosphatase\u2010\u03b1 enzymatic activity for gene therapy of glycogen storage disease type Ia"],"prefix":"10.1002","volume":"42","author":[{"given":"Lisa","family":"Zhang","sequence":"first","affiliation":[{"name":"Section on Cellular Differentiation, Division of Translational Medicine Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health  Bethesda Maryland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jun\u2010Ho","family":"Cho","sequence":"additional","affiliation":[{"name":"Section on Cellular Differentiation, Division of Translational Medicine Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health  Bethesda Maryland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Irina","family":"Arnaoutova","sequence":"additional","affiliation":[{"name":"Section on Cellular Differentiation, Division of Translational Medicine Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health  Bethesda Maryland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brian C.","family":"Mansfield","sequence":"additional","affiliation":[{"name":"Section on Cellular Differentiation, Division of Translational Medicine Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health  Bethesda Maryland"},{"name":"Foundation Fighting Blindness  Columbia Maryland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4004-6516","authenticated-orcid":false,"given":"Janice Y.","family":"Chou","sequence":"additional","affiliation":[{"name":"Section on Cellular Differentiation, Division of Translational Medicine Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health  Bethesda Maryland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2019,2,22]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrendo.2010.189"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.2174\/1566524024605798"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2014.128"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF02679990"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2017.01.003"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1517\/14712598.2011.578067"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.25717"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2013.06.014"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2010.64"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddv230"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.15252\/embj.201694699"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2014.09.003"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0243-7"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1243490"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature19057"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110486200"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng0696-203"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1006819"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.11.6144"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pep.2015.02.002"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.2174\/138920309789630534"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1089\/hum.2011.106"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1089\/hum.2009.157"}],"container-title":["Journal 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