{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T06:11:34Z","timestamp":1789020694943,"version":"build-2803163510"},"reference-count":92,"publisher":"SAGE Publications","issue":"9","license":[{"start":{"date-parts":[[2019,9,1]],"date-time":"2019-09-01T00:00:00Z","timestamp":1567296000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Human Gene Therapy"],"published-print":{"date-parts":[[2019,9]]},"abstract":"<jats:p>\n                    Krabbe disease is an inherited neurodegenerative disease caused by mutations in the\n                    <jats:italic toggle=\"yes\">galactosylceramidase<\/jats:italic>\n                    gene. In the infantile form, patients die before 3 years of age. Systemic adeno-associated virus serotype 9 (AAV9) gene therapy was recently shown to reverse the disease course in human patients in another lethal infantile neurodegenerative disease. To explore AAV9 therapy for Krabbe disease, we engineered a codon-optimized AAV9 galactosylceramidase vector. We further incorporated features to allow AAV9-derived galactosylceramidase to more efficiently cross the blood\u2013brain barrier and be secreted from transduced cells. We tested the optimized vector by a single systemic injection in the twitcher mouse, an authentic Krabbe disease model. Untreated twitcher mice showed characteristic neuropathology and motion defects. They died prematurely with a median life span of 41 days. Intravenous injection in 2-day-old twitcher mice reduced central and peripheral neuropathology and significantly improved the gait pattern and body weight. Noticeably, the median life span was extended to 150 days. Intraperitoneal injection in 6- to 12-day-old twitcher mice also significantly improved the motor function, body weight, and median life span (to 104 days). Our results far exceed the \u226470 days median life span seen in all reported stand-alone systemic AAV therapies. Our study highlights the importance of vector engineering for Krabbe disease gene therapy. The engineered vector warrants further development.\n                  <\/jats:p>","DOI":"10.1089\/hum.2019.008","type":"journal-article","created":{"date-parts":[[2019,6,11]],"date-time":"2019-06-11T07:21:21Z","timestamp":1560237681000},"page":"1039-1051","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":27,"title":["An Engineered Galactosylceramidase Construct Improves AAV Gene Therapy for Krabbe Disease in Twitcher Mice"],"prefix":"10.1177","volume":"30","author":[{"given":"Xiufang","family":"Pan","sequence":"first","affiliation":[{"name":"Department of Molecular Microbiology and Immunology, School of Medicine, University of Missouri, Columbia, Missouri"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott A.","family":"Sands","sequence":"additional","affiliation":[{"name":"Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, Kansas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongping","family":"Yue","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology and Immunology, School of Medicine, University of Missouri, Columbia, Missouri"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keqing","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology and Immunology, School of Medicine, University of Missouri, Columbia, Missouri"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven M.","family":"LeVine","sequence":"additional","affiliation":[{"name":"Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, Kansas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongsheng","family":"Duan","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology and Immunology, School of Medicine, University of Missouri, Columbia, Missouri"},{"name":"Department of Neurology, School of Medicine, University of Missouri, Columbia, Missouri"},{"name":"Department of Veterinary Biomedical Sciences, College of Veterinary Medicine, University of Missouri, Columbia, Missouri"},{"name":"Department of Biomedical, Biological &amp; Chemical Engineering, College of Engineering, University of Missouri, Columbia, Missouri."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2019,9,17]]},"reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.23743"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/39.1-2.74"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.23791"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.23888"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pediatrneurol.2011.05.007"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199804163381605"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.23782"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.23822"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.23752"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1750-3639.1995.tb00601.x"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/0006-8993(80)90159-6"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/103.3.695"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.6382609"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.1996.0136"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-4547(20000415)60:2<231::AID-JNR12>3.0.CO;2-E"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.05-3826fje"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2009.09.017"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.6383-09.2010"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.1002583"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.gt.3301495"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1002\/jgm.719"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-801238-3.95711-8"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1089\/hum.2017.172"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1002\/jgm.3015"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2005.04.019"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2004.12.020"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1802-11.2011"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2012.153"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2015.145"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2014.12.300"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4199-14.2015"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.23882"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2018.01.009"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.gene.2015.06.049"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.mt.6300026"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2011.05.005"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.1016\/0378-1119(89)90209-6"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1002\/emmm.201202083"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471-4159.1996.66031118.x"},{"key":"e_1_3_4_41_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-61779-343-1_15"},{"key":"e_1_3_4_42_2","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.20169"},{"key":"e_1_3_4_43_2","doi-asserted-by":"publisher","DOI":"10.1016\/0736-5748(94)90075-2"},{"key":"e_1_3_4_44_2","doi-asserted-by":"publisher","DOI":"10.1006\/nbdi.2002.0527"},{"key":"e_1_3_4_45_2","first-page":"18","article-title":"Automated measurement of amphetamine-induced focused stereotypy in rats and harmaline-induced tremor in mice: an introduction to the force plate actimeter","volume":"22","author":"Katner S","year":"2007","unstructured":"Katner S, , Nikolaidis N, , Markham J, et al. Automated measurement of amphetamine-induced focused stereotypy in rats and harmaline-induced tremor in mice: an introduction to the force plate actimeter. Curr Sep Drug Dev, 2007; 22:18\u201320.","journal-title":"Curr Sep Drug Dev"},{"key":"e_1_3_4_46_2","first-page":"3","article-title":"Boosting brain uptake of a therapeutic antibody by reducing its affinity for a transcytosis target","author":"Yu YJ","year":"2011","unstructured":"Yu YJ, , Zhang Y, , Kenrick M, et al. Boosting brain uptake of a therapeutic antibody by reducing its affinity for a transcytosis target. Sci Transl Med, 2011; 3.","journal-title":"Sci Transl Med"},{"key":"e_1_3_4_47_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0702170104"},{"key":"e_1_3_4_48_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1222742110"},{"key":"e_1_3_4_49_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2009.07.011"},{"key":"e_1_3_4_50_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.coviro.2016.07.006"},{"key":"e_1_3_4_51_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.conb.2017.12.011"},{"key":"e_1_3_4_52_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4939-3271-9_10"},{"key":"e_1_3_4_53_2","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2014.68"},{"key":"e_1_3_4_54_2","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.1515"},{"key":"e_1_3_4_55_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2017.10.017"},{"key":"e_1_3_4_56_2","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2011.98"},{"key":"e_1_3_4_57_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.07232-11"},{"key":"e_1_3_4_58_2","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2011.34"},{"key":"e_1_3_4_59_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddv168"},{"key":"e_1_3_4_60_2","doi-asserted-by":"publisher","DOI":"10.1089\/hum.2012.029"},{"key":"e_1_3_4_61_2","doi-asserted-by":"publisher","DOI":"10.1038\/gt.2014.17"},{"key":"e_1_3_4_62_2","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.1610"},{"key":"e_1_3_4_63_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3000830"},{"key":"e_1_3_4_64_2","first-page":"192","article-title":"Single systemic AAV micro-dystrophin therapy ameliorates muscular dystrophy in young adult Duchenne muscular dystrophy dogs for up to two years","volume":"25","author":"Hakim CH","year":"2017","unstructured":"Hakim CH, , Kodippili K, , Jenkins G, et al. Single systemic AAV micro-dystrophin therapy ameliorates muscular dystrophy in young adult Duchenne muscular dystrophy dogs for up to two years. Mol Ther, 2017; 25:192\u2013193.","journal-title":"Mol Ther"},{"key":"e_1_3_4_65_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1706198"},{"key":"e_1_3_4_66_2","doi-asserted-by":"publisher","DOI":"10.1089\/humc.2015.132"},{"key":"e_1_3_4_67_2","doi-asserted-by":"publisher","DOI":"10.1089\/hum.2018.012"},{"key":"e_1_3_4_68_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2018.07.011"},{"key":"e_1_3_4_69_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2015.05.035"},{"key":"e_1_3_4_70_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.sbi.2016.07.004"},{"key":"e_1_3_4_71_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2017.03.037"},{"key":"e_1_3_4_72_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0712147105"},{"key":"e_1_3_4_73_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.78.9.5838"},{"key":"e_1_3_4_74_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2017.11.013"},{"key":"e_1_3_4_75_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2018.02.032"},{"key":"e_1_3_4_76_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2018.01.010"},{"key":"e_1_3_4_77_2","doi-asserted-by":"publisher","DOI":"10.1007\/s13205-016-0595-3"},{"key":"e_1_3_4_78_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.gt.3303029"},{"key":"e_1_3_4_79_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.mt.6300081"},{"key":"e_1_3_4_80_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1416660111"},{"key":"e_1_3_4_81_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtm.2018.03.004"},{"key":"e_1_3_4_82_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtm.2018.07.006"},{"key":"e_1_3_4_83_2","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.3440"},{"key":"e_1_3_4_84_2","doi-asserted-by":"publisher","DOI":"10.1038\/nn.4593"},{"key":"e_1_3_4_85_2","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2015.231"},{"key":"e_1_3_4_86_2","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2016.84"},{"key":"e_1_3_4_87_2","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.23874"},{"key":"e_1_3_4_88_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF02834075"},{"key":"e_1_3_4_89_2","doi-asserted-by":"publisher","DOI":"10.1006\/geno.1996.0220"},{"key":"e_1_3_4_90_2","doi-asserted-by":"publisher","DOI":"10.1006\/geno.1997.4744"},{"key":"e_1_3_4_91_2","doi-asserted-by":"publisher","DOI":"10.1089\/hum.2017.151"},{"key":"e_1_3_4_92_2","doi-asserted-by":"publisher","DOI":"10.5966\/sctm.2015-0317"},{"key":"e_1_3_4_93_2","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.201505850"}],"container-title":["Human Gene Therapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.sagepub.com\/doi\/full-xml\/10.1089\/hum.2019.008","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1089\/hum.2019.008","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1089\/hum.2019.008","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T11:15:35Z","timestamp":1779102935000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/10.1089\/hum.2019.008"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,9]]},"references-count":92,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2019,9]]}},"alternative-id":["10.1089\/hum.2019.008"],"URL":"https:\/\/doi.org\/10.1089\/hum.2019.008","relation":{},"ISSN":["1043-0342","1557-7422"],"issn-type":[{"value":"1043-0342","type":"print"},{"value":"1557-7422","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,9]]}}}