Orphanet Journal of Rare Diseases | Research Advances in Enzyme Replacement and Gene Therapies for MPS IVA

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This article systematically summarizes the latest progress in enzyme replacement therapy (ERT) and gene therapy (GT) for mucopolysaccharidosis IVA (MPS IVA), focusing on the effects of different vector systems and promoter combinations on disease phenotypes, while proposing novel strategies to enhance enzyme stability and targeted delivery.

 

Literature Overview
Published in Orphanet Journal of Rare Diseases, this review article 'Recent advances in mucopolysaccharidosis IVA treatment' discusses therapeutic strategies and research progress in mucopolysaccharidosis IVA (Morquio A syndrome), emphasizing enzyme replacement therapy (ERT), gene therapy (GT), and emerging antisense RNA and mitochondrial function modulation approaches. The article examines the efficacy, immunogenicity, and tissue-targeting capabilities of viral vectors (AAV, LV, CRISPR/Cas9) and non-viral vectors in animal models, while highlighting current limitations in skeletal improvement and the potential value of combination therapies.

Background Knowledge
MPS IVA is a rare lysosomal storage disorder caused by mutations in the GALNS gene, leading to deficiency of N-acetylgalactosamine-6-sulfatase (GALNS) and subsequent accumulation of keratan sulfate (KS) and chondroitin-6-sulfate (C6S). The disease primarily affects the skeletal system, causing progressive bone dysplasia and multiorgan involvement. Currently, enzyme replacement therapy (ERT) is the only FDA-approved treatment, but its efficacy in bone tissues is limited by rapid enzyme clearance and poor penetration into avascular cartilage regions. As an emerging strategy, gene therapy (GT) using AAV, LV, and CRISPR/Cas9 platforms has achieved significant GALNS activity restoration in mouse and rat models.

 

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Research Methods and Experiments
This study systematically analyzed various gene therapy and enzyme replacement approaches in MPS IVA models, including AAV vectors driven by different promoters (CAG, TBG, LMTP, LBTP), LV-mediated HSC gene modification, and CRISPR/Cas9 gene editing strategies. The research team evaluated GALNS enzyme activity, KS levels, bone and cartilage pathology, immune response, and vector safety in mouse and rat models.

Key Conclusions and Perspectives

• AAV-mediated GALNS expression effectively restores enzyme activity in liver and bone tissues, though efficacy is significantly influenced by promoters and serotypes, with the CAG promoter showing broader tissue expression.
• LV vectors successfully transduce HSCs and promote GALNS expression in blood cells and bones, but require further optimization for effective bone repair.
• CRISPR/Cas9 system enables targeted repair of GALNS gene mutations, restoring enzyme activity and reducing KS levels without significant off-target effects, demonstrating potential curative capabilities.
• Utilizing bone-targeting peptides (e.g., D8) and PEGylated hydrogels enhances ERT stability, tissue penetration, and prolongs therapeutic duration.
• MSC-EVs as natural enzyme carriers exhibit excellent bone targeting capabilities with immunomodulatory and regenerative potential.
• Antisense RNA and circRNA strategies effectively correct aberrant splicing caused by deep intronic variants, providing precision treatment options for specific mutations.
• Mitochondrial dysfunction and chronic inflammatory responses have been identified as novel pathogenic mechanisms in MPS IVA, establishing theoretical foundations for combination therapies.

Significance and Future Directions
The article emphasizes the potential of combining multiple interventions (e.g., GT+AAV+CNP, ASO+ERT) to improve bone pathology and systemic disease manifestations. Developing novel bone-targeting vectors, optimizing promoters and expression systems, and integrating immunomodulation with mitochondrial function restoration will facilitate more comprehensive disease modification and long-term therapeutic efficacy.

 

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Conclusion
This article reviews recent advances in MPS IVA treatment, including ERT, GT, and emerging ASO and mitochondrial modulation strategies. While current therapies demonstrate enzyme activity restoration and substrate clearance in multiple tissues, significant limitations remain in bone repair. AAV and LV vectors effectively restore enzyme expression under different promoters but require optimization for cartilage and growth plate penetration. CRISPR/Cas9-mediated gene repair shows curative potential in vitro and in mouse models, yet requires further in vivo validation. Antisense RNA and circRNA approaches offer high-specificity correction of aberrant splicing, enabling personalized treatment pathways for specific mutations. Future research should focus on combination therapies, bone-targeted delivery systems, immune tolerance induction, and mitochondrial function modulation to achieve comprehensive phenotypic correction. The ultimate goal is to improve quality of life and survival outcomes for MPS IVA patients through multidimensional interventions.

 

Andrés Felipe Leal and Harry Pachajoa. Recent advances in mucopolysaccharidosis IVA treatment. Orphanet Journal of Rare Diseases.