Enzyme replacement therapy in mucopolysaccharidosis I: altered distribution and targeting of alpha-L-iduronidase in immunized rats.

Enzyme replacement therapy (ERT) has been developed and trialed for the treatment of human lysosomal storage disorder patients. The viability of ERT for the treatment of these severe multiple pathology disorders has subsequently been established. However, in both animal model studies and human clinical trials, some individuals have been shown to develop an immune response to the replacement protein. This potential complication for treatment has been investigated by the infusion of recombinant human alpha-L-iduronidase (rh-alpha-L-iduronidase) into nonimmune and immunized rats to simulate mucopolysaccharidosis type I ERT in the presence of different levels of antibody. In rats with high antibody titers to rh-alpha-L-iduronidase (titer 1,024,000) there was evidence of altered organ distribution and subcellular targeting when compared to either lower titer immunized rats (titers less than 64,000) or nonimmune rats (titers 512-1024). In addition, hypersensitivity reactions were observed for high titer rats (titer 1,024,000) during rh-alpha-L-iduronidase infusion, but not for the other two treatment groups. A rat with an antibody titer of 64,000 had only minor changes in subcellular targeting and organ distribution when infused with rh-alpha-L-iduronidase. This implied that a high level of antibody was required to effect changes in alpha-L-iduronidase enzyme targeting and distribution. Notably, in the high titer rats, the antibody produced appeared to increase the tissue and subcellular level of rh-alpha-L-iduronidase specific activity. This suggested that antibody production may not always result in an adverse effect on ERT.