{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T11:51:03Z","timestamp":1779105063005,"version":"3.51.4"},"reference-count":58,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,2,28]],"date-time":"2026-02-28T00:00:00Z","timestamp":1772236800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Austrian MPS Society, A Cure for Robert, Inc."},{"name":"The Morquio Community and Angelo Cali Family"},{"DOI":"10.13039\/100018298","name":"The Bennett Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100018298","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Fighting For Freya Foundation"},{"name":"Scarlett Griffith Foundation"},{"name":"Nemours Funds"},{"DOI":"10.13039\/100000002","name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health","doi-asserted-by":"publisher","award":["1R01HD102545-01A1"],"award-info":[{"award-number":["1R01HD102545-01A1"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Mucopolysaccharidosis IVA (MPS IVA) is caused by the accumulation of undegraded glycosaminoglycans due to the deficiency of the N-acetylgalactosamine-6-sulfate sulfatase (GALNS) enzyme. MPS IVA manifests as progressive systemic skeletal dysplasia. Gene therapy (GT) is potentially a one-time treatment in which the enzyme is continuously produced, circulated, and delivered to target tissues. However, immune responses to gene products can diminish therapeutic efficacy. We hypothesized that oral delivery of tolerogenic peptides induces immune tolerance to human GALNS (hGALNS) in MPS IVA mice, enhancing therapeutic efficacy. Neonatal mice deficient in mouse GALNS (mGALNS) were treated orally with three T-cell\/B-cell epitope peptides or hGALNS protein on alternate days from day 3 after birth to day 20 before intravenous injection with AAV9 vectors encoding human GALNS on day 30. The results are encouraging, with anti-hGALNS antibodies undetectable in the plasma of orally administered peptide groups. hGALNS enzyme activities in plasma and tissues were higher in the orally treated groups than in the non-tolerized control group. Keratan sulfate levels in plasma, liver, and bone were normalized. Complete correction for heart vacuolization was achieved in peptide-treated groups, and partial correction for bone pathology was observed in all GT-treated groups. Overall, oral tolerance induction using immunodominant peptides promises to significantly enhance the efficacy of AAV-GT for MPS IVA.<\/jats:p>","DOI":"10.3390\/ijms27052278","type":"journal-article","created":{"date-parts":[[2026,3,2]],"date-time":"2026-03-02T10:24:34Z","timestamp":1772447074000},"page":"2278","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["AAV Gene Therapy for MPS IVA with Induction of Immune Tolerance via Oral Administration of Epitope Peptides of N-Acetylgalactosamine-6-sulfate Sulfatase"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-7994-2032","authenticated-orcid":false,"given":"Sampurna","family":"Saikia","sequence":"first","affiliation":[{"name":"Department of Biomedical Research, Nemours Children\u2019s Health, Wilmington, DE 19803, USA"},{"name":"Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5307-3658","authenticated-orcid":false,"given":"Yasuhiko","family":"Ago","sequence":"additional","affiliation":[{"name":"Department of Biomedical Research, Nemours Children\u2019s Health, Wilmington, DE 19803, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7511-6620","authenticated-orcid":false,"given":"Fnu","family":"Nidhi","sequence":"additional","affiliation":[{"name":"Department of Biomedical Research, Nemours Children\u2019s Health, Wilmington, DE 19803, USA"},{"name":"Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shaukat","family":"Khan","sequence":"additional","affiliation":[{"name":"Department of Biomedical Research, Nemours Children\u2019s Health, Wilmington, DE 19803, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0258-7821","authenticated-orcid":false,"given":"Zhengyu","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Biomedical Research, Nemours Children\u2019s Health, Wilmington, DE 19803, USA"},{"name":"Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0673-2160","authenticated-orcid":false,"given":"Shunji","family":"Tomatsu","sequence":"additional","affiliation":[{"name":"Department of Biomedical Research, Nemours Children\u2019s Health, Wilmington, DE 19803, USA"},{"name":"Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA"},{"name":"Department of Pediatrics, Shimane University, Izumo 693-8501, Japan"},{"name":"Department of Pediatrics, Graduate School of Medicine, Gifu University, Gifu 501-1193, Japan"},{"name":"Department of Pediatrics, Thomas Jefferson University, Philadelphia, PA 19107, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,28]]},"reference":[{"key":"ref_1","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. 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