Molecular markers for the follow-up of enzyme replacement therapy in mucopolysaccharidosis VI disease.

MPS VI (mucopolysaccharidosis type VI) is a lysosomal storage disease in which deficient activity of the enzyme N-acetylgalactosamine 4-sulfatase [ASB (arylsulfatase B)] impairs the stepwise degradation of the GAG (glycosaminoglycan) dermatan sulfate. Clinical studies of ERT (enzyme replacement therapy) by using rhASB (recombinant human ASB) have been reported with promising results. The release of GAG into the urine is currently used as a biomarker of disease, reflecting in some cases disease severity and in all cases therapeutic responsiveness. Using RNA studies in four Italian patients undergoing ERT, we observed that TNFalpha (tumour necrosis factor alpha) might be a biomarker for MPS VI responsive to therapy. In addition to its role as a potential biomarker, TNFalpha expression could provide insights into the possible pathophysiological mechanisms underlying the mucopolysaccharidoses

MPS VI disease: evaluation of molecular markers for the follow-up of enzyme replacement therapy

Mucopolysaccharidosis type VI is a lysosomal storage disease in which deficient activity of the enzyme N-acetylgalactosamine 4-sulfatase (arylsulfatase B, ASB) impairs the stepwise degradation of the glycosaminoglycan (GAG) dermatan sulfate resulting in striking osseous changes. Enzyme replacement therapy (ERT) involving the infusion of a human recombinant enzyme was started, with good results (1). Currently the GAG release into the urine is used as the only biochemical marker reflecting therapeutic responsiveness. Recently, in MPS I patients the heparin cofactor II-thrombin complex (HCII-T) concentration in the serum was reported to be a good biomarker for the follow-up of therapy (2). In the present study, using the real time RT-PCR analysis on RNA samples prepared from blood of four MPS VI patients undergoing ERT, we explored several molecules (TNF-α, SPARC, MMP9, TIMP-1, IL-1β, HCII and Ccl3) as potential biomarkers for the response to therapy. Interestingly, in our MPS VI subjects HCII, previously demonstrated to be low at the protein level in MPS I patients (2), was also low at the RNA level, as compared to normal control. Among the tested molecules only TNF-α resulted to be up-regulated before therapy, presenting a 2.29-fold increase in its expression versus the normal control. The elevation of the chondrodestructive TNF-α cytokine, produced by MPS chondrocytes, synoviocytes and macrophages, reflects most likely the severity of chondral damage. TNF-α showed a decrease in its expression already at one month from treatment resulting to be a biomarker for the follow-up of the therapy in the MPS VI; however, its role needs to be confirmed in larger studies