Mucopolysaccharidosis VI: Therapeutic strategies and perspectives

Mucopolysaccharidosis VI, also known as Maroteaux-Lamy syndrome, is a lysosomal storage disorder (LSD) caused by pathogenic mutations in the ARSB gene, resulting in arylsulfatase (ARSB) deficiency and the lysosomal accumulation of dermatan sulfate (DS) and chondroitin 4-sulfate (C4S). DS and C4S accumulation leads to multisystemic symptoms in MPS VI patients in cartilage, bone, heart valves, cornea, liver, and respiratory tract. Currently, enzyme replacement therapy (ERT) is the only approved treatment for patients with MPS VI, providing clinical benefits that include increased survival and improved quality of life. However, ERT has a limited impact on bone manifestations. Significant advances have been made in gene therapy (GT) using classical adeno-associated virus and the CRISPR/Cas9 system, providing promising alternatives in MPS VI. Importantly, hematopoietic stem cell transplantation (HSCT) in combination with GT may also offer a novel alternative. Additionally, substrate reduction therapy with odiparcil, immunomodulation, and stop codon read-through therapies have been explored in MPS VI. Future directions in MPS VI should include targeting cellular alterations, such as mitochondrial dysfunction, exploring cartilage-targeting alternatives, and implementing pharmacological chaperones. This manuscript highlights recent progress and emerging strategies for treating MPS VI.