ENZYME REPLACEMENT THERAPY IN MUCOPOLYSACCHARIDOSIS-VI - EVIDENCE FORIMMUNE-RESPONSES AND ALTERED EFFICACY OF TREATMENT IN ANIMAL-MODELS

Enzyme replacement therapy (ERT) can potentially result in an immunolo gical response to the introduced protein. The immunological response b y Mucopolysaccharidosis type VI (MPS VI) cats to recombinant human N-a cetylgalactosamine 4-sulfatase (rh4S) ERT has been investigated. Plasm a antibody titres to rh4S were detected in untreated MPS VI and normal control cats, but the antibody titres to rh4S were higher in ERT trea ted MPS VI cats. The reactivity by cats to rh4S did not appear to be j ust due to species cross reactivity, as plasma antibodies from normal control, MPS VI and MPS VI ERT cats reacted equally with feline and hu man 4-sulfatase. Normal control and MPS VI human plasma also had antib ody titres to rh4S. Plasma antibodies to rh4S, from an ERT treated cat , could be temporarily removed from circulation by enzyme infusion, co nfirming specificity for rh4S and indicating a possible window for ERT in the absence of antibody. In enzyme distribution studies with H-3-r h4S, evidence of altered targeting, and enzyme inactivation and degrad ation were observed in high compared to low titre rats. In high titre rats, the observed loss of H-3-label from vacuolar organelles of the l iver may represent either degradation of antibody bound H-3-rh4S for r eutilisation within the liver, or antigen presentation. The developmen t of high titre antibody may have a detrimental effect on the efficacy of ERT. (C) 1997 Elsevier Science B.V.