In Vivo Direct Lentiviral Gene Therapy Improves Disease Pathology in a Mucopolysaccharidosis IVA Murine Model

Authors

Betul Celik, Thomas Jefferson University
Estera Rintz
Shaukat Khan, Thomas Jefferson University
Andrés F. Leal, Thomas Jefferson University
Fnu Nidhi, Thomas Jefferson University
Shunji Tomatsu, Thomas Jefferson UniversityFollow

Document Type

Article

Publication Date

6-16-2025

Comments

This article is the author’s final published version in Molecular Therapy Methods and Clinical Development, Volume 33, Issue 3, 2025, Article number 101514.

The published version is available at https://doi.org/10.1016/j.omtm.2025.101514. Copyright © 2025 The Author(s).

Abstract

Mucopolysaccharidosis IVA (MPS IVA) is an autosomal recessive disorder that causes the accumulation of keratan sulfate (KS) and chondroitin-6-sulfate in bone and cartilage. This results in progressive skeletal dysplasia, with no effective treatment available. Our study hypothesized that direct lentiviral vector (LV) gene therapy could produce active enzymes from transduced cells, impacting bone and cartilage lesions in MPS IVA. We developed LVs carrying the GALNS gene under three promoters: ubiquitous (CBh), collagen type II (COL2A1), and Mac-1 integrin subunit (CD11b). At the newborn stage and 4 weeks, Galns-knockout mice received intravenous injections at different doses (5 × 10⁹, 1 × 10¹⁰, or 1 × 10¹¹ TU/kg). Our analysis included vector copy numbers, enzyme activity, glycosaminoglycan levels, bone and heart pathology, and bone morphology. Results showed that intravenously infused high doses of LVs with the CBh promoter in newborn mice yielded the highest enzyme activity and normalized KS levels in plasma and tissues, improving bone and heart pathology without liver toxicity. We noted an increase in anti-GALNS antibodies, suggesting an immune response to the therapy. These findings underscore the potential of in vivo direct LV gene therapy as a promising approach for treating MPS IVA and similar skeletal disorders.

Recommended Citation

Celik, Betul; Rintz, Estera; Khan, Shaukat; Leal, Andrés F.; Nidhi, Fnu; and Tomatsu, Shunji, "In Vivo Direct Lentiviral Gene Therapy Improves Disease Pathology in a Mucopolysaccharidosis IVA Murine Model" (2025). Department of Pediatrics Faculty Papers. Paper 177.
https://jdc.jefferson.edu/pedsfp/177

Creative Commons License

This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

PubMed ID

40677837

Language

English