Antibodies to recombinant human alpha-L-iduronidase prevent disease correction in cortical bone in MPS I mice

Mucopolysaccharidosis I (MPS I) is a lysosomal storage disorder caused by deficiency of the enzyme α-L-iduronidase (IDUA). Failure of enzyme replacement therapy (ERT) to treat skeletal disease may be due to development of anti-IDUA antibodies, found previously to alter tissue distribution of ERT in animal models. To test this hypothesis, immunocompromised (non-obese diabetic [NOD]-severe combined immunodeficiency [SCID]) MPS I mice were treated with weekly ERT from birth (ERT alone). Some mice also received weekly injections of rabbit immunoglobulin G (IgG) against IDUA (immunized rabbit immune globulin [IRIG]) concomitant with ERT, imitating antibodies developed in patients (ERT+IRIG). Mice treated with ERT+IRIG showed lower IDUA activity and higher disease burden than mice treated with ERT alone in most tissues. Femora were harvested at 20 weeks for ex vivo microcomputed tomography (μCT). Femoral cortical bone thickness and cortical bone area in MPS I mice were greater than in unaffected mice. Mice treated with ERT alone had values that were statistically indistinguishable from carrier mice, while mice that received ERT+IRIG had no significant differences compared to vehicle-treated MPS I mice. The data suggests that immune-modulatory or immune-suppressive therapy to prevent or reduce the humoral immune response against ERT may improve treatment of skeletal disease due to MPS I.