{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T15:40:34Z","timestamp":1783698034182,"version":"3.55.0"},"reference-count":36,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2022,8,23]],"date-time":"2022-08-23T00:00:00Z","timestamp":1661212800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["R01NS102624"],"award-info":[{"award-number":["R01NS102624"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurologic Disorders and Stroke","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"crossref"}]},{"name":"National Institute on Diabetes, Digestive and Kidney Disease"},{"DOI":"10.13039\/100000055","name":"National Institute on Deafness and Communication Disorders","doi-asserted-by":"crossref","award":["R01 DK067859"],"award-info":[{"award-number":["R01 DK067859"]}],"id":[{"id":"10.13039\/100000055","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000055","name":"National Institute on Deafness and Communication Disorders","doi-asserted-by":"crossref","award":["R03 DC011840"],"award-info":[{"award-number":["R03 DC011840"]}],"id":[{"id":"10.13039\/100000055","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000055","name":"National Institute on Deafness and Communication Disorders","doi-asserted-by":"crossref","award":["R01 DC012552"],"award-info":[{"award-number":["R01 DC012552"]}],"id":[{"id":"10.13039\/100000055","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000055","name":"National Institute on Deafness and Communication Disorders","doi-asserted-by":"crossref","award":["R01 DC014437"],"award-info":[{"award-number":["R01 DC014437"]}],"id":[{"id":"10.13039\/100000055","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,1,13]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Mucopolysaccharidosis type IIIB (MPS IIIB) is an autosomal recessive lysosomal storage disease caused by mutations in the gene that encodes the protein N-acetyl-glucosaminidase (NAGLU). Defective NAGLU activity results in aberrant retention of heparan sulfate within lysosomes leading to progressive central nervous system (CNS) degeneration. Intravenous treatment options are limited by the need to overcome the blood\u2013brain barrier and gain successful entry into the CNS. Additionally, we have demonstrated that AAV8 provides a broader transduction area in the MPS IIIB mouse brain compared with AAV5, 9 or rh10. A triple-capsid mutant (tcm) modification of AAV8 further enhanced GFP reporter expression and distribution. Using the MPS IIIB mouse model, we performed a study using either intracranial six site or intracisterna magna injection of AAVtcm8-codon-optimized (co)-NAGLU using untreated MPS IIIB mice as controls to assess disease correction. Disease correction was evaluated based on enzyme activity, heparan sulfate storage levels, CNS lysosomal signal intensity, coordination, activity level, hearing and survival. Both histologic and enzymatic assessments show that each injection method results in supranormal levels of NAGLU expression in the brain. In this study, we have shown correction of lifespan and auditory deficits, increased CNS NAGLU activity and reduced lysosomal storage levels of heparan sulfate following AAVtcm8-coNAGLU administration and partial correction of NAGLU activity in several peripheral organs in the murine model of MPS IIIB.<\/jats:p>","DOI":"10.1093\/hmg\/ddac209","type":"journal-article","created":{"date-parts":[[2022,8,23]],"date-time":"2022-08-23T15:24:56Z","timestamp":1661268296000},"page":"417-430","source":"Crossref","is-referenced-by-count":6,"title":["Disease correction in mucopolysaccharidosis type IIIB mice by intraparenchymal or cisternal delivery of a capsid modified AAV8 codon-optimized <i>NAGLU<\/i> vector"],"prefix":"10.1093","volume":"32","author":[{"given":"Courtney J","family":"Rouse","sequence":"first","affiliation":[{"name":"Department of Medicine, University of Florida College of Medicine , Gainesville, FL , USA"},{"name":"Lacerta Therapeutics , Alachua, FL , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimberley","family":"Hawkins","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Florida College of Medicine , Gainesville, FL , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadia","family":"Kabbej","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Florida College of Medicine , Gainesville, FL , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justin","family":"Dalugdug","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Florida College of Medicine , Gainesville, FL , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aishwarya","family":"Kunta","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Florida College of Medicine , Gainesville, FL , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mi-Jung","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Aging and Geriatric Research, University of Florida , Gainesville, FL , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinichi","family":"Someya","sequence":"additional","affiliation":[{"name":"Department of Aging and Geriatric Research, University of Florida , Gainesville, FL , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zachary","family":"Herbst","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Washington , Seattle, WA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Gelb","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Washington , Seattle, WA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabella","family":"Dinelli","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Florida College of Medicine , Gainesville, FL , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Butterworth","sequence":"additional","affiliation":[{"name":"Lacerta Therapeutics , Alachua, FL , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darin J","family":"Falk","sequence":"additional","affiliation":[{"name":"Lacerta Therapeutics , Alachua, FL , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erinn","family":"Rosenkrantz","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Florida College of Medicine , Gainesville, FL , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hamza","family":"Elmohd","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Florida College of Medicine , Gainesville, FL , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hamid","family":"Khaledi","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Washington , Seattle, WA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samar","family":"Mowafy","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Washington , Seattle, WA , USA"},{"name":"Pharmaceutical Chemistry Department, Misr International University , Cairo , Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederick","family":"Ashby","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Florida College of Medicine , Gainesville, FL , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2148-2868","authenticated-orcid":false,"given":"Coy D","family":"Heldermon","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Florida College of Medicine , Gainesville, FL , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,8,23]]},"reference":[{"key":"2023011922200361100_ref1","doi-asserted-by":"crossref","DOI":"10.3390\/ijms21082975","article-title":"Intravenous enzyme replacement therapy in mucopolysaccharidoses: clinical effectiveness and limitations","volume":"21","author":"Parini","year":"2020","journal-title":"Int. J. Mol. Sci."},{"key":"2023011922200361100_ref2","article-title":"Methods of neurodevelopmental assessment in children with neurodegenerative disease: Sanfilippo syndrome","volume":"13","author":"Delaney","year":"2013","journal-title":"JIMD Rep."},{"issue":"Suppl 1","key":"2023011922200361100_ref3","first-page":"133","article-title":"Mucopolysaccharidosis III (Sanfilippo syndrome)- disease presentation and experimental therapies","volume":"12","author":"Gilkes","year":"2014","journal-title":"Pediatr. Endocrinol. Rev."},{"key":"2023011922200361100_ref4","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1186\/s13023-017-0717-y","article-title":"Mortality in patients with Sanfilippo syndrome","volume":"12","author":"Lavery","year":"2017","journal-title":"Orphanet J. Rare Dis."},{"key":"2023011922200361100_ref5","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.ymgmr.2015.11.006","article-title":"Preferred transduction with AAV8 and AAV9 via thalamic administration in the MPS IIIB model: a comparison of four rAAV serotypes","volume":"6","author":"Gilkes","year":"2016","journal-title":"Mol. Genet. Metab. Rep."},{"key":"2023011922200361100_ref6","doi-asserted-by":"crossref","first-page":"712","DOI":"10.1016\/S1474-4422(17)30169-2","article-title":"Intracerebral gene therapy in children with mucopolysaccharidosis type IIIB syndrome: an uncontrolled phase 1\/2 clinical trial","volume":"16","author":"Tardieu","year":"2017","journal-title":"Lancet Neurol."},{"key":"2023011922200361100_ref7","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1093\/brain\/awx311","article-title":"Macrophage enzyme and reduced inflammation drive brain correction of mucopolysaccharidosis IIIB by stem cell gene therapy","volume":"141","author":"Holley","year":"2018","journal-title":"Brain"},{"key":"2023011922200361100_ref8","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.ymgme.2018.12.003","article-title":"Final results of the phase 1\/2, open-label clinical study of intravenous recombinant human N-acetyl-alpha-d-glucosaminidase (SBC-103) in children with mucopolysaccharidosis IIIB","volume":"126","author":"Whitley","year":"2019","journal-title":"Mol. Genet. Metab."},{"key":"2023011922200361100_ref9","doi-asserted-by":"crossref","first-page":"792","DOI":"10.1016\/j.ymthe.2016.12.025","article-title":"Near-complete correction of profound Metabolomic impairments corresponding to functional benefit in MPS IIIB mice after IV rAAV9-hNAGLU gene delivery","volume":"25","author":"Fu","year":"2017","journal-title":"Mol. Ther."},{"key":"2023011922200361100_ref10","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1089\/humc.2013.208","article-title":"Feasibility and safety of systemic rAAV9-hNAGLU delivery for treating mucopolysaccharidosis IIIB: toxicology, biodistribution, and immunological assessments in primates","volume":"25","author":"Murrey","year":"2014","journal-title":"Hum. Gene Ther. Clin. Dev."},{"key":"2023011922200361100_ref11","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1007\/s40259-017-0234-5","article-title":"Adeno-associated virus (AAV) as a vector for gene therapy","volume":"31","author":"Naso","year":"2017","journal-title":"BioDrugs"},{"key":"2023011922200361100_ref12","article-title":"Mucopolysaccharidosis IIIB confers enhanced neonatal intracranial transduction by AAV8 but not by 5, 9 or rh10","volume":"23","author":"Gilkes","year":"2015","journal-title":"Gene Ther."},{"key":"2023011922200361100_ref13","doi-asserted-by":"crossref","first-page":"S227","DOI":"10.1016\/S1525-0016(16)35598-8","article-title":"AAV8 is preferential candidate for neonatal gene transfer in murine MPS IIIB model","volume":"22","author":"Gilkes","year":"2014","journal-title":"Mol. Ther."},{"key":"2023011922200361100_ref14","doi-asserted-by":"crossref","first-page":"S128","DOI":"10.1016\/S1525-0016(16)34667-6","article-title":"Differences in AAV serotype dependent distribution and tropism exist within the CNS of wild type and mutant mice in the MPSIIIB mouse model","volume":"21","author":"Gilkes","year":"2013","journal-title":"Mol. Ther."},{"key":"2023011922200361100_ref15","article-title":"Site-specific modifications to AAV8 capsid yields enhanced brain transduction in the neonatal MPS IIIB mouse","volume":"28","author":"Gilkes","year":"2020","journal-title":"Gene Ther."},{"key":"2023011922200361100_ref16","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1038\/gt.2013.14","article-title":"Disease correction by combined neonatal intracranial AAV and systemic lentiviral gene therapy in Sanfilippo syndrome type B mice","volume":"20","author":"Heldermon","year":"2013","journal-title":"Gene Ther."},{"key":"2023011922200361100_ref17","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1038\/mt.2010.17","article-title":"Therapeutic efficacy of bone marrow transplant, intracranial AAV-mediated gene therapy, or both in the mouse model of MPS IIIB","volume":"18","author":"Heldermon","year":"2010","journal-title":"Mol Ther"},{"key":"2023011922200361100_ref18","doi-asserted-by":"crossref","first-page":"915","DOI":"10.1016\/j.dib.2016.06.052","article-title":"Dataset and standard operating procedure for newborn screening of six lysosomal storage diseases: by tandem mass spectrometry","volume":"8","author":"Elliott","year":"2016","journal-title":"Data Brief"},{"key":"2023011922200361100_ref19","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1016\/j.ymgme.2016.05.015","article-title":"Pilot study of newborn screening for six lysosomal storage diseases using tandem mass spectrometry","volume":"118","author":"Elliott","year":"2016","journal-title":"Mol. Genet. Metab."},{"key":"2023011922200361100_ref20","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/j.ymgme.2020.08.007","article-title":"Therapy development for the mucopolysaccharidoses: updated consensus recommendations for neuropsychological endpoints","volume":"131","author":"Lee","year":"2020","journal-title":"Mol. Genet. Metab."},{"key":"2023011922200361100_ref21","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/j.ymgme.2020.07.006","article-title":"Comparative analysis of brain pathology in heparan sulphate storing mucopolysaccharidoses","volume":"131","author":"Derrick-Roberts","year":"2020","journal-title":"Mol. Genet. Metab."},{"key":"2023011922200361100_ref22","doi-asserted-by":"crossref","first-page":"3495","DOI":"10.1038\/s41467-021-23903-5","article-title":"Altered heparan sulfate metabolism during development triggers dopamine-dependent autistic-behaviours in models of lysosomal storage disorders","volume":"12","author":"De Risi","year":"2021","journal-title":"Nat. Commun."},{"key":"2023011922200361100_ref23","doi-asserted-by":"crossref","first-page":"14505","DOI":"10.1073\/pnas.96.25.14505","article-title":"Mouse model of Sanfilippo syndrome type B produced by targeted disruption of the gene encoding alpha-N-acetylglucosaminidase","volume":"96","author":"Li","year":"1999","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2023011922200361100_ref24","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1038\/360749a0","article-title":"Reversal of pathology in murine mucopolysaccharidosis type VII by somatic cell gene transfer","volume":"360","author":"Wolfe","year":"1992","journal-title":"Nature"},{"key":"2023011922200361100_ref25","doi-asserted-by":"crossref","first-page":"1025","DOI":"10.1038\/mt.2011.34","article-title":"Correction of neurological disease of mucopolysaccharidosis IIIB in adult mice by rAAV9 trans-blood-brain barrier gene delivery","volume":"19","author":"Fu","year":"2011","journal-title":"Mol Ther"},{"key":"2023011922200361100_ref26","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1042\/BJ20130845","article-title":"Insulin-like growth factor II peptide fusion enables uptake and lysosomal delivery of alpha-N-acetylglucosaminidase to mucopolysaccharidosis type IIIB fibroblasts","volume":"458","author":"Kan","year":"2014","journal-title":"Biochem J"},{"key":"2023011922200361100_ref27","doi-asserted-by":"crossref","first-page":"14870","DOI":"10.1073\/pnas.1416660111","article-title":"Delivery of an enzyme-IGFII fusion protein to the mouse brain is therapeutic for mucopolysaccharidosis type IIIB","volume":"111","author":"Kan","year":"2014","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2023011922200361100_ref28","doi-asserted-by":"crossref","first-page":"S55","DOI":"10.1016\/j.ymgme.2012.11.133","article-title":"Comparing IC6 and thalamic AAV5 injections on MPS IIIB model","volume":"108","author":"Kolarich","year":"2013","journal-title":"Mol. Genet. Metab."},{"key":"2023011922200361100_ref29","doi-asserted-by":"crossref","first-page":"14505","DOI":"10.1073\/pnas.96.25.14505","article-title":"Mouse model of Sanfilippo syndrome type B produced by targeted disruption of the gene encoding N\u2212acetylglucosaminidase","volume":"96","author":"Li","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2023011922200361100_ref30","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1038\/gt.2015.111","article-title":"Mucopolysaccharidosis IIIB confers enhanced neonatal intracranial transduction by AAV8 but not by 5, 9 or rh10","volume":"23","author":"Gilkes","year":"2016","journal-title":"Gene Ther."},{"key":"2023011922200361100_ref31","doi-asserted-by":"crossref","first-page":"e67680","DOI":"10.1371\/journal.pone.0067680","article-title":"Capsid serotype and timing of injection determines AAV transduction in the neonatal mice brain","volume":"8","author":"Chakrabarty","year":"2013","journal-title":"PLoS One"},{"key":"2023011922200361100_ref32","doi-asserted-by":"crossref","first-page":"69","DOI":"10.3390\/ijns6030069","article-title":"Evaluation of multiple methods for quantification of glycosaminoglycan biomarkers in newborn dried blood spots from patients with severe and attenuated mucopolysaccharidosis-I","volume":"6","author":"Herbst","year":"2020","journal-title":"Int. J. Neonatal. Screen."},{"key":"2023011922200361100_ref33","doi-asserted-by":"crossref","first-page":"11721","DOI":"10.1021\/acs.analchem.0c01750","article-title":"Tandem mass spectrometry enzyme assays for multiplex detection of 10-mucopolysaccharidoses in dried blood spots and fibroblasts","volume":"92","author":"Khaledi","year":"2020","journal-title":"Anal. Chem."},{"key":"2023011922200361100_ref34","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1111\/j.1399-0004.1985.tb00217.x","article-title":"4-Methylumbelliferyl alpha-N-acetylglucosaminidase activity for diagnosis of Sanfilippo B disease","volume":"27","author":"Marsh","year":"1985","journal-title":"Clin. Genet."},{"key":"2023011922200361100_ref35","first-page":"676","article-title":"Treatment of murine mucopolysaccharidosis type VII by syngeneic bone marrow transplantation in neonates","volume":"68","author":"Sands","year":"1993","journal-title":"Lab Invest."},{"key":"2023011922200361100_ref36","doi-asserted-by":"crossref","first-page":"e772","DOI":"10.1371\/journal.pone.0000772","article-title":"Development of sensory, motor and behavioral deficits in the murine model of Sanfilippo syndrome type B","volume":"2","author":"Heldermon","year":"2007","journal-title":"PLoS One"}],"container-title":["Human Molecular Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/hmg\/advance-article-pdf\/doi\/10.1093\/hmg\/ddac209\/46371416\/ddac209.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/hmg\/article-pdf\/32\/3\/417\/48691144\/ddac209.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/hmg\/article-pdf\/32\/3\/417\/48691144\/ddac209.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,19]],"date-time":"2023-01-19T22:20:53Z","timestamp":1674166853000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/hmg\/article\/32\/3\/417\/6673965"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,23]]},"references-count":36,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2022,8,23]]},"published-print":{"date-parts":[[2023,1,13]]}},"URL":"https:\/\/doi.org\/10.1093\/hmg\/ddac209","relation":{},"ISSN":["0964-6906","1460-2083"],"issn-type":[{"value":"0964-6906","type":"print"},{"value":"1460-2083","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2023,2,1]]},"published":{"date-parts":[[2022,8,23]]}}}