Recent advances in mucopolysaccharidosis IVA treatment

TL;DR

This paper reviews recent progress in treating Morquio A syndrome, a rare genetic disorder, focusing on new therapies like gene editing and enzyme stabilization.

Contribution

The paper highlights novel therapeutic strategies including gene therapy, pharmacological chaperones, and antisense-based approaches for MPS IVA.

Findings

Gene therapy using AAV and CRISPR/Cas9 has shown promise in restoring GALNS activity in animal models.

Pharmacological chaperones like ezetimibe stabilize GALNS in vitro.

Antisense therapies offer new ways to correct genetic mutations in MPS IVA.

Abstract

Mucopolysaccharidosis IVA (MPS IVA, Morquio A syndrome) is a rare lysosomal storage disorder caused by mutations in the GALNS gene, resulting in N-acetylgalactosamine-6-sulfatase (GALNS) deficiency and accumulation of keratan sulfate and chondroitin-6-sulfate. MPS IVA primarily affects the skeletal system, leading to progressive dysplasia and multi-organ involvement. Although enzyme replacement therapy (ERT) with elosulfase alfa is currently the only approved treatment, its clinical benefit on bone pathology is limited due to rapid clearance and poor penetration into avascular cartilage. Strategies to enhance enzyme stability and targeting, such as PEGylated hydrogels and extracellular vesicles, have shown promise in enhancing the biodistribution and stability of GALNS, while pharmacological chaperones, including ezetimibe, pranlukast, and bromocriptine, seem to stabilize GALNS in vitro. Promisingly, gene therapy (GT) has demonstrated significant preclinical progress using adeno-associated virus (AAV), lentiviral (LV), and CRISPR/Cas9 platforms. For instance, AAV vectors employing bone-targeting peptides and tandem promoters improve skeletal manifestations in murine and rat models. Similarly, recent ex vivo LV-based GT studies have opened new avenues in the treatment of MPS IVA. Furthermore, CRISPR/nCas9-based strategies targeting safe harbor loci have successfully restored GALNS activity in MPS IVA fibroblasts and mouse models supporting the notion that gene editing may represent a potential therapeutic approach. On the other hand, antisense-based therapies using modified U7 small nuclear RNAs and circular RNAs offer novel approaches to correct pseudoexon activation from deep-intronic variants while expanding the therapeutic alternatives in MPS IVA. Importantly, recent evidence revealed that mitochondrial dysfunction in chondrocytes may contribute to the pathology of MPS IVA, uncovering new targets beyond GALNS enzyme activity recovery. This review highlights recent advances in the treatment of MPS IVA and discusses new directions to improve outcomes in MPS IVA treatment.

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