{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:48:12Z","timestamp":1787028492242,"version":"build-2736575974"},"reference-count":61,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2022,10,21]],"date-time":"2022-10-21T00:00:00Z","timestamp":1666310400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Austrian MPS society","award":["1R01HD102545-01A1"],"award-info":[{"award-number":["1R01HD102545-01A1"]}]},{"name":"A Cure for Robert, Inc","award":["1R01HD102545-01A1"],"award-info":[{"award-number":["1R01HD102545-01A1"]}]},{"name":"The Carol Ann Foundation","award":["1R01HD102545-01A1"],"award-info":[{"award-number":["1R01HD102545-01A1"]}]},{"name":"Angelo R. Cali &amp; Mary V. Cali Family Foundation, Inc.","award":["1R01HD102545-01A1"],"award-info":[{"award-number":["1R01HD102545-01A1"]}]},{"name":"The Vain and Harry Fish Foundation, Inc.","award":["1R01HD102545-01A1"],"award-info":[{"award-number":["1R01HD102545-01A1"]}]},{"name":"The Bennett Foundation","award":["1R01HD102545-01A1"],"award-info":[{"award-number":["1R01HD102545-01A1"]}]},{"name":"Jacob Randall Foundation","award":["1R01HD102545-01A1"],"award-info":[{"award-number":["1R01HD102545-01A1"]}]},{"name":"Nemours Funds","award":["1R01HD102545-01A1"],"award-info":[{"award-number":["1R01HD102545-01A1"]}]},{"name":"Institutional Development Award from the Eunice Kennedy Shriver National Institute of Child Health &amp; Human Development of the National Institutes of Health (NICHD)","award":["1R01HD102545-01A1"],"award-info":[{"award-number":["1R01HD102545-01A1"]}]},{"name":"REGENXBIO Inc.","award":["1R01HD102545-01A1"],"award-info":[{"award-number":["1R01HD102545-01A1"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Adeno-associated virus (AAV) vector-based therapies can effectively correct some disease pathology in murine models with mucopolysaccharidoses. However, immunogenicity can limit therapeutic effect as immune responses target capsid proteins, transduced cells, and gene therapy products, ultimately resulting in loss of enzyme activity. Inherent differences in male versus female immune response can significantly impact AAV gene transfer. We aim to investigate sex differences in the immune response to AAV gene therapies in mice with mucopolysaccharidosis IVA (MPS IVA). MPS IVA mice, treated with different AAV vectors expressing human N-acetylgalactosamine 6-sulfate sulfatase (GALNS), demonstrated a more robust antibody response in female mice resulting in subsequent decreased GALNS enzyme activity and less therapeutic efficacy in tissue pathology relative to male mice. Under thyroxine-binding globulin promoter, neutralizing antibody titers in female mice were approximately 4.6-fold higher than in male mice, with GALNS enzyme activity levels approximately 6.8-fold lower. Overall, male mice treated with AAV-based gene therapy showed pathological improvement in the femur and tibial growth plates, ligaments, and articular cartilage as determined by contrasting differences in pathology scores compared to females. Cardiac histology revealed a failure to normalize vacuolation in females, in contrast, to complete correction in male mice. These findings promote the need for further determination of sex-based differences in response to AAV-mediated gene therapy related to developing treatments for MPS IVA.<\/jats:p>","DOI":"10.3390\/ijms232012693","type":"journal-article","created":{"date-parts":[[2022,10,24]],"date-time":"2022-10-24T04:40:36Z","timestamp":1666586436000},"page":"12693","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Sex Difference Leads to Differential Gene Expression Patterns and Therapeutic Efficacy in Mucopolysaccharidosis IVA Murine Model Receiving AAV8 Gene Therapy"],"prefix":"10.3390","volume":"23","author":[{"given":"Matthew","family":"Piechnik","sequence":"first","affiliation":[{"name":"Nemours\/Alfred I. DuPont Hospital for Children, Wilmington, DE 19803, USA"},{"name":"Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paige C.","family":"Amendum","sequence":"additional","affiliation":[{"name":"Nemours\/Alfred I. DuPont Hospital for Children, Wilmington, DE 19803, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuki","family":"Sawamoto","sequence":"additional","affiliation":[{"name":"Nemours\/Alfred I. DuPont Hospital for Children, Wilmington, DE 19803, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Molly","family":"Stapleton","sequence":"additional","affiliation":[{"name":"Nemours\/Alfred I. DuPont Hospital for Children, Wilmington, DE 19803, USA"},{"name":"Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA"},{"name":"Philadelphia College of Osteopathic Medicine, Philadelphia, PA 19131, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaukat","family":"Khan","sequence":"additional","affiliation":[{"name":"Nemours\/Alfred I. DuPont Hospital for Children, Wilmington, DE 19803, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nidhi","family":"Fnu","sequence":"additional","affiliation":[{"name":"Nemours\/Alfred I. DuPont Hospital for Children, Wilmington, DE 19803, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victor","family":"\u00c1lvarez","sequence":"additional","affiliation":[{"name":"Nemours\/Alfred I. DuPont Hospital for Children, Wilmington, DE 19803, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelica Maria Herre\u00f1o","family":"Pachon","sequence":"additional","affiliation":[{"name":"Nemours\/Alfred I. DuPont Hospital for Children, Wilmington, DE 19803, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivier","family":"Danos","sequence":"additional","affiliation":[{"name":"REGENXBIO Inc., Rockville, MD 20850, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph T.","family":"Bruder","sequence":"additional","affiliation":[{"name":"REGENXBIO Inc., Rockville, MD 20850, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Subha","family":"Karumuthil-Melethil","sequence":"additional","affiliation":[{"name":"REGENXBIO Inc., Rockville, MD 20850, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0673-2160","authenticated-orcid":false,"given":"Shunji","family":"Tomatsu","sequence":"additional","affiliation":[{"name":"Nemours\/Alfred I. DuPont Hospital for Children, Wilmington, DE 19803, USA"},{"name":"Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA"},{"name":"Department of Pediatrics, Shimane University, Izumo 693-8501, Shimane, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/j.ymgme.2016.11.007","article-title":"Mucopolysaccharidosis IVA and glycosaminoglycans","volume":"120","author":"Khan","year":"2017","journal-title":"Mol. Genet. Metab."},{"key":"ref_2","first-page":"141","article-title":"Morquio A Syndrome: Diagnosis and Current and Future Therapies","volume":"12","author":"Tomatsu","year":"2014","journal-title":"Pediatr. Endocrinol. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/j.ymgme.2016.04.005","article-title":"Activity of daily living for Morquio A syndrome","volume":"118","author":"Yasuda","year":"2016","journal-title":"Mol. Genet. Metab."},{"key":"ref_4","first-page":"59","article-title":"Mortality in Patients with Morquio Syndrome A","volume":"Volume 15","author":"Lavery","year":"2014","journal-title":"JIMD Reports"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Sawamoto, K., Gonz\u00e1lez, J.V., Piechnik, M., Otero, F.J., Couce, M.L., Suzuki, Y., and Tomatsu, S. (2020). Mucopolysaccharidosis IVA: Diagnosis, Treatment, and Management. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21041517"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1279","DOI":"10.1517\/21678707.2015.1086640","article-title":"Enzyme replacement therapy for treating mucopolysaccharidosis type IVA (Morquio A syndrome): Effect and limitations","volume":"3","author":"Tomatsu","year":"2015","journal-title":"Expert Opin. Orphan Drugs"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1137","DOI":"10.1007\/s40262-014-0173-y","article-title":"Pharmacokinetic and pharmacodynamic evaluation of elosulfase alfa, an enzyme replacement therapy in patients with Morquio A syndrome","volume":"53","author":"Qi","year":"2014","journal-title":"Clin. Pharmacokinet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1038\/s10038-019-0604-6","article-title":"Effect of enzyme replacement therapy on the growth of patients with Morquio A","volume":"64","author":"Doherty","year":"2019","journal-title":"J. Hum. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.ymgmr.2013.11.002","article-title":"Long-term therapeutic efficacy of allogenic bone marrow transplantation in a patient with mucopolysaccharidosis IVA","volume":"1","author":"Chinen","year":"2014","journal-title":"Mol. Genet. Metab. Rep."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2104","DOI":"10.1016\/j.bbmt.2016.08.015","article-title":"Allogeneic Hematopoietic Stem Cell Transplantation in Thirty-Four Pediatric Cases of Mucopolysaccharidosis\u2014A Ten-Year Report from the China Children Transplant Group","volume":"22","author":"Wang","year":"2016","journal-title":"Biol. Blood Marrow Transpl."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.ymgme.2015.09.011","article-title":"Hematopoietic stem cell transplantation for Morquio A syndrome","volume":"117","author":"Yabe","year":"2016","journal-title":"Mol. Genet. Metab."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1186\/s13052-018-0565-y","article-title":"Gene therapy for mucopolysaccharidoses: In vivo and ex vivo approaches","volume":"44","author":"Fraldi","year":"2018","journal-title":"Ital. J. Pediatr."},{"key":"ref_13","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":"ref_14","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1038\/mt.2009.255","article-title":"Effect of Genome Size on AAV Vector Packaging","volume":"18","author":"Wu","year":"2010","journal-title":"Mol. Ther."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"9933","DOI":"10.1128\/JVI.79.15.9933-9944.2005","article-title":"Packaging Capacity of Adeno-Associated Virus Serotypes: Impact of Larger Genomes on Infectivity and Postentry Steps","volume":"79","author":"Grieger","year":"2005","journal-title":"J. Virol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"S10","DOI":"10.1038\/sj.gt.3302364","article-title":"Immune responses to gene therapy vectors: Influence on vector function and effector mechanisms","volume":"11","author":"Bessis","year":"2004","journal-title":"Gene Ther."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3335","DOI":"10.1182\/blood-2012-10-462200","article-title":"Therapeutic levels of FVIII following a single peripheral vein administration of rAAV vector encoding a novel human factor VIII variant","volume":"121","author":"McIntosh","year":"2013","journal-title":"Blood"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2357","DOI":"10.1056\/NEJMoa1108046","article-title":"Adenovirus-Associated Virus Vector\u2013Mediated Gene Transfer in Hemophilia B","volume":"365","author":"Nathwani","year":"2011","journal-title":"N. Engl. J. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1994","DOI":"10.1056\/NEJMoa1407309","article-title":"Long-Term Safety and Efficacy of Factor IX Gene Therapy in Hemophilia B","volume":"371","author":"Nathwani","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Piechnik, M., Sawamoto, K., Ohnishi, H., Kawamoto, N., Ago, Y., and Tomatsu, S. (2020). Evading the AAV Immune Response in Mucopolysaccharidoses. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21103433"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"103728","DOI":"10.1016\/j.cellimm.2017.12.002","article-title":"Liver induced transgene tolerance with AAV vectors","volume":"342","author":"Keeler","year":"2017","journal-title":"Cell. Immunol."},{"key":"ref_22","first-page":"141","article-title":"AAV-Mediated Liver-Directed Gene Therapy","volume":"Volume 807","author":"Snyder","year":"2011","journal-title":"Adeno-Associated Virus: Methods and Protocols"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.omtm.2020.05.015","article-title":"Liver-Targeted AAV8 Gene Therapy Ameliorates Skeletal and Cardiovascular Pathology in a Mucopolysaccharidosis IVA Murine Model","volume":"18","author":"Sawamoto","year":"2020","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1182\/blood-2002-09-2889","article-title":"Sex significantly influences transduction of murine liver by recombinant adeno-associated viral vectors through an androgen-dependent pathway","volume":"102","author":"Davidoff","year":"2003","journal-title":"Blood"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1470","DOI":"10.1038\/mt.2013.95","article-title":"Mouse Gender Influences Brain Transduction by Intravascularly Administered AAV9","volume":"21","author":"Maguire","year":"2013","journal-title":"Mol. Ther."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1038\/nri.2016.90","article-title":"Sex differences in immune responses","volume":"16","author":"Klein","year":"2016","journal-title":"Nat. Rev. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1016\/j.cbpa.2012.11.021","article-title":"Gender differences in the immune system activities of sea urchin Paracentrotus lividus","volume":"164","author":"Arizza","year":"2012","journal-title":"Comp. Biochem. Physiol. Part A Mol. Integr. Physiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1477","DOI":"10.1534\/genetics.108.093971","article-title":"X-Linked Variation in Immune Response in Drosophila melanogaster","volume":"183","author":"Clark","year":"2009","journal-title":"Genetics"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1111\/j.1365-2656.2006.01193.x","article-title":"Sex and testosterone effects on growth, immunity and melanin coloration of nestling Eurasian kestrels","volume":"76","author":"Fargallo","year":"2006","journal-title":"J. Anim. Ecol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0145-305X(99)00057-9","article-title":"Gender differences and individual variation in the immune system of the scorpionfly Panorpa vulgaris (Insecta: Mecoptera)","volume":"24","author":"Kurtz","year":"2000","journal-title":"Dev. Comp. Immunol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1006\/gcen.1999.7370","article-title":"Sexual Dimorphism in Phagocytic Activity of Wall Lizard\u2019s Splenic Macrophages and Its Control by Sex Steroids","volume":"116","author":"Mondal","year":"1999","journal-title":"Gen. Comp. Endocrinol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1095\/biolreprod.107.063545","article-title":"Testosterone Reduces Macrophage Expression in the Mouse of Toll-Like Receptor 4, a Trigger for Inflammation and Innate Immunity","volume":"78","author":"Rettew","year":"2008","journal-title":"Biol. Reprod."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"656","DOI":"10.4049\/jimmunol.132.2.656","article-title":"Sex-associated differences in the regulation of immune responses controlled by the MHC of the mouse","volume":"132","author":"Weinstein","year":"1984","journal-title":"J. Immunol."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Zuk, M. (2009). The Sicker Sex. PLOS Pathog., 5.","DOI":"10.1371\/journal.ppat.1000267"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"194","DOI":"10.3389\/fmicb.2011.00194","article-title":"Innate Immune Responses to AAV Vectors","volume":"2","author":"Rogers","year":"2011","journal-title":"Front. Microbiol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1038\/gt.2008.137","article-title":"Enhancing transduction of the liver by adeno-associated viral vectors","volume":"16","author":"Nathwani","year":"2008","journal-title":"Gene Ther."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.1182\/blood-2003-01-0182","article-title":"Expansion of CMV-specific CD8+CD45RA+CD27- T cells in B-cell chronic lymphocytic leukemia","volume":"102","author":"Mackus","year":"2003","journal-title":"Blood"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2043","DOI":"10.1128\/jvi.76.5.2043-2053.2002","article-title":"Ubiquitination of both Adeno-Associated Virus Type 2 and 5 Capsid Proteins Affects the Transduction Efficiency of Recombinant Vectors","volume":"76","author":"Yan","year":"2002","journal-title":"J. Virol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1128\/jvi.70.1.520-532.1996","article-title":"Transduction with recombinant adeno-associated virus for gene therapy is limited by leading-strand synthesis","volume":"70","author":"Fisher","year":"1996","journal-title":"J. Virol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"S192","DOI":"10.1016\/j.ymthe.2005.07.037","article-title":"Sex and Estrous Cycle Stage Influence the Efficiency of AAV-Mediated Gene Transfer in the Rodent Brain","volume":"11","author":"Dodge","year":"2005","journal-title":"Mol. Ther."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Torcia, M.G., Nencioni, L., Clemente, A.M., Civitelli, L., Celestino, I., Limongi, D., Fadigati, G., Perissi, E., Cozzolino, F., and Garaci, E. (2012). Sex Differences in the Response to Viral Infections: TLR8 and TLR9 Ligand Stimulation Induce Higher IL10 Production in Males. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0039853"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1050","DOI":"10.1002\/bies.201200099","article-title":"Sex influences immune responses to viruses, and efficacy of prophylaxis and treatments for viral diseases","volume":"34","author":"Klein","year":"2012","journal-title":"BioEssays"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Klein, S., and Roberts, C. (2010). Sex Steroid Receptors in Immune Cells. Sex Hormones and Immunity to Infection, Springer.","DOI":"10.1007\/978-3-642-02155-8"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1089\/hum.2017.150","article-title":"Unraveling the Complex Story of Immune Responses to AAV Vectors Trial After Tri-al","volume":"28","author":"Vandamme","year":"2017","journal-title":"Hum. Gene Ther."},{"key":"ref_45","first-page":"S104","article-title":"CHAMPI-ONS: A Phase 1\/2 Clinical Trial with Dose Escalation of SB-913 ZFN-Mediated in Vivo Human Genome Editing for Treatment of MPS II (Hunter Syndrome)","volume":"126","author":"Muenzer","year":"2019","journal-title":"Mol. Genet. Metab."},{"key":"ref_46","unstructured":"Office USGA (2022, July 06). National Institutes of Health: Better Oversight Needed to Help Ensure Continued Progress Including Women in Health Research, Available online: https:\/\/www.gao.gov\/products\/gao-16-13."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s12276-018-0187-x","article-title":"It is time to integrate sex as a variable in preclinical and clinical studies","volume":"50","author":"Lee","year":"2018","journal-title":"Exp. Mol. Med."},{"key":"ref_48","first-page":"255","article-title":"Balance of the Sexes: Addressing Sex Differences in Preclinical Re-search","volume":"89","author":"Zakiniaeiz","year":"2016","journal-title":"Yale J. Biol. Med."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1016\/S0140-6736(18)32995-7","article-title":"Factors affecting sex-related reporting in medical research: A cross-disciplinary bibliometric analysis","volume":"393","author":"Sugimoto","year":"2019","journal-title":"Lancet"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"3349","DOI":"10.1093\/hmg\/ddg366","article-title":"Mouse model of N-acetylgalactosamine-6-sulfate sulfatase deficiency (Galns\u2212\/\u2212) produced by targeted disruption of the gene defective in Morquio A disease","volume":"12","author":"Tomatsu","year":"2003","journal-title":"Hum. Mol. Genet."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2007","DOI":"10.1089\/104303401753204571","article-title":"Various Cells Retrovirally Transduced withN-Acetylgalactosoamine-6-Sulfate Sulfatase Correct Morquio Skin FibroblastsIn Vitro","volume":"12","author":"Toietta","year":"2001","journal-title":"Hum. Gene Ther."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"31237","DOI":"10.1074\/jbc.M801586200","article-title":"Tetrasulfated Disaccharide Unit in Heparan Sulfate: Enzymatic formation and tissue distribution","volume":"283","author":"Mochizuki","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1002\/bmc.760","article-title":"Analytical method for determination of disaccharides derived from keratan sulfates in human serum and plasma by high-performance liquid chromatography\/turbo-ionspray ionization tandem mass spectrometry","volume":"21","author":"Oguma","year":"2007","journal-title":"Biomed. Chromatogr."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.ab.2007.05.016","article-title":"Analytical method for the determination of disaccharides derived from keratan, heparan, and dermatan sulfates in human serum and plasma by high-performance liquid chromatography\/turbo ionspray ionization tandem mass spectrometry","volume":"368","author":"Oguma","year":"2007","journal-title":"Anal. Biochem."},{"key":"ref_55","first-page":"S66","article-title":"Chondroitin 6-sulfate as a novel biomarker for mucopolysaccharidosis IVA and VII","volume":"114","author":"Kubaski","year":"2015","journal-title":"Mol. Genet. Metab."},{"key":"ref_56","first-page":"1","article-title":"Di-sulfated Keratan Sulfate as a Novel Biomarker for Mucopolysaccharidosis II, IVA, and IVB","volume":"21","author":"Shimada","year":"2015","journal-title":"JIMD Rep."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1007\/s10545-016-9981-6","article-title":"Newborn screening for mucopolysaccharidoses: A pilot study of measurement of glycosaminoglycans by tandem mass spectrometry","volume":"40","author":"Kubaski","year":"2016","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"961","DOI":"10.1093\/hmg\/ddg119","article-title":"Production of MPS VII mouse (Gus(tm(hE540A x mE536A)Sly)) doubly tolerant to human and mouse beta-glucuronidase","volume":"12","author":"Tomatsu","year":"2003","journal-title":"Hum. Mol. Genet."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"3321","DOI":"10.1093\/hmg\/ddi364","article-title":"Development of MPS IVA mouse (Galnstm(hC79S\u00b7mC76S)slu) tolerant to human N-acetylgalactosamine-6-sulfate sulfatase","volume":"14","author":"Tomatsu","year":"2005","journal-title":"Hum. Mol. Genet."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1094","DOI":"10.1038\/mt.2010.32","article-title":"Enhancement of Drug Delivery: Enzyme-replacement Therapy for Murine Morquio A Syndrome","volume":"18","author":"Tomatsu","year":"2010","journal-title":"Mol. Ther."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/j.ymgme.2014.05.013","article-title":"Enzyme replacement therapy in newborn mucopolysaccharidosis IVA mice: Early treatment rescues bone lesions?","volume":"114","author":"Tomatsu","year":"2015","journal-title":"Mol. Genet. Metab."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/20\/12693\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:59:04Z","timestamp":1760144344000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/20\/12693"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,21]]},"references-count":61,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2022,10]]}},"alternative-id":["ijms232012693"],"URL":"https:\/\/doi.org\/10.3390\/ijms232012693","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,10,21]]}}}