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