AAV Gene Therapy for MPS IVA with Induction of Immune Tolerance via Oral Administration of Epitope Peptides of N-Acetylgalactosamine-6-sulfate Sulfatase

Authors

Sampurna Saikia, Thomas Jefferson University
Yasuhiko Ago, Thomas Jefferson University
Fnu Nidhi, Thomas Jefferson UniversityFollow
Shaukat Khan, Thomas Jefferson University
Zhengyu Ma, Thomas Jefferson University
Shunji Tomatsu, Thomas Jefferson UniversityFollow

Document Type

Article

Publication Date

2-28-2026

Comments

This article is the author's final published version in International Journal of Molecular Sciences, Volume 27, Issue 5, February 2026, Article Number 2278.

The published version is available at https://doi.org/10.3390/ijms27052278. Copyright © 2026 By The Authors.

Abstract

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.

Recommended Citation

Saikia, Sampurna; Ago, Yasuhiko; Nidhi, Fnu; Khan, Shaukat; Ma, Zhengyu; and Tomatsu, Shunji, "AAV Gene Therapy for MPS IVA with Induction of Immune Tolerance via Oral Administration of Epitope Peptides of N-Acetylgalactosamine-6-sulfate Sulfatase" (2026). Department of Pediatrics Faculty Papers. Paper 196.
https://jdc.jefferson.edu/pedsfp/196

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 License.

PubMed ID

41828510

Language

English