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Peer-reviewedCC BY 4.0International Journal of Molecular Sciences

Induction of Oral Immune Tolerance Enables Sequential AAV9/AAV8 Gene Therapy in Mucopolysaccharidosis IVA

  • Sampurna Saikia1,2
  • Krishna Sai Musini2
  • Shaukat Khan2
  • Shunji Tomatsu2,3,4,5,6,7
7 affiliations
  1. 1Department of Pediatrics, Oregon Health and Science University, Portland, OR 97239, USA
  2. 2Department of Biomedical Research, Nemours Children’s Health, Wilmington, DE 19803, USA
  3. 3Department of Pediatrics, Shimane University, Izumo 693-8501, Japan
  4. 4Department of Pediatrics, Graduate School of Medicine, Gifu University, Gifu 501-1193, Japan
  5. 5Department of Pediatrics, Thomas Jefferson University, Philadelphia, PA 19107, USA
  6. 6Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA
  7. 7DuPont Experimental Station, Bldg. E400 #5205, 200 Powder Mill Rd., Wilmington, DE 19803, USA
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Abstract

Mucopolysaccharidosis IVA (MPS IVA) results from deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS), leading to progressive keratan sulfate accumulation, and current treatments have limited efficacy. Although adeno-associated virus (AAV) gene therapy can restore systemic enzyme activity, immune responses to the transgene and viral capsid restrict durability and prevent vector re-administration. We evaluated a combined strategy of antigen-specific oral immune tolerance and sequential AAV serotype delivery. Neonatal MPS IVA mice received a mixture of three immunodominant GALNS-derived T- and B-cell epitopes on alternate days for 20 days, followed by AAV9 at 4 weeks and redosing with either AAV9 or AAV8 at 10 weeks. Peptide-treated tolerized MPS IVA mice showed a 2–3-fold increase in circulating GALNS activity after the first dose and a 7–8-fold increase after redosing, whereas non-tolerized MPS IVA mice developed anti-GALNS antibodies that reduced enzyme levels. No cross-reactive neutralizing antibodies were detected between AAV9 and AAV8. Peptide-treated mice showed normalization of plasma and hepatic keratan sulfate (KS) and significant improvements in skeletal and cardiac histopathology, with the greatest benefit in the peptide-treated AAV9→AAV8 group. These findings demonstrate that oral immune tolerance enables safe AAV re-administration, enhances systemic enzyme bioavailability, and improves tissue correction, supporting a clinically translatable approach for durable treatment of MPS IVA.

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Cite

BibTeXRIS
BibTeX
@article{saikia2026induction,
  title = {{Induction of Oral Immune Tolerance Enables Sequential AAV9/AAV8 Gene Therapy in Mucopolysaccharidosis IVA}},
  author = {Sampurna Saikia and Krishna Sai Musini and Shaukat Khan and Shunji Tomatsu},
  journal = {International Journal of Molecular Sciences},
  year = {2026},
  month = oct,
  doi = {10.3390/ijms27219553},
  url = {https://www.mdpi.com/1422-0067/27/21/9553},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Induction of Oral Immune Tolerance Enables Sequential AAV9/AAV8 Gene Therapy in Mucopolysaccharidosis IVA
AU  - Sampurna Saikia
AU  - Krishna Sai Musini
AU  - Shaukat Khan
AU  - Shunji Tomatsu
PY  - 2026
DA  - 2026/10/26
JO  - International Journal of Molecular Sciences
DO  - 10.3390/ijms27219553
UR  - https://www.mdpi.com/1422-0067/27/21/9553
AB  - Mucopolysaccharidosis IVA (MPS IVA) results from deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS), leading to progressive keratan sulfate accumulation, and current treatments have limited efficacy. Although adeno-associated virus (AAV) gene therapy can restore systemic enzyme activity, immune responses to the transgene and viral capsid restrict durability and prevent vector re-administration. We evaluated a combined strategy of antigen-specific oral immune tolerance and sequential AAV serotype delivery. Neonatal MPS IVA mice received a mixture of three immunodominant GALNS-derived T- and B-cell epitopes on alternate days for 20 days, followed by AAV9 at 4 weeks and redosing with either AAV9 or AAV8 at 10 weeks. Peptide-treated tolerized MPS IVA mice showed a 2–3-fold increase in circulating GALNS activity after the first dose and a 7–8-fold increase after redosing, whereas non-tolerized MPS IVA mice developed anti-GALNS antibodies that reduced enzyme levels. No cross-reactive neutralizing antibodies were detected between AAV9 and AAV8. Peptide-treated mice showed normalization of plasma and hepatic keratan sulfate (KS) and significant improvements in skeletal and cardiac histopathology, with the greatest benefit in the peptide-treated AAV9→AAV8 group. These findings demonstrate that oral immune tolerance enables safe AAV re-administration, enhances systemic enzyme bioavailability, and improves tissue correction, supporting a clinically translatable approach for durable treatment of MPS IVA.
SN  - 1422-0067
ER  -