Immune response hinders therapy for lysosomal storage diseases

Abstract

Enzyme replacement therapy (ERT) for the lysosomal storage disease mucopolysaccharidosis I (MPS I) involves i.v. injection of alpha-l-iduronidase, which can be taken up by cells throughout the body. While a significant immune response to ERT has been shown in patients with MPS I, little is known about what effect anti-enzyme antibodies have on treatment efficacy. In this issue of the JCI, Dickson et al. demonstrate that anti-enzyme antibodies inhibit enzyme uptake and substantially limit the therapeutic efficacy of ERT in canines with MPS I (see the related article beginning on page 2868). Furthermore, the induction of immune tolerance--via oral delivery of cyclosporine A and azathioprine for two months at the time of initiation of ERT with recombinant human alpha-L-iduronidase--improved enzyme uptake in organs. Therefore, transient immunosuppression may enhance ERT for lysosomal storage diseases.

Figure 1. Anti-IDUA antibodies can inhibit the uptake of the therapeutic enzyme IDUA during enzyme replacement therapy for the lysosomal storage disease MPS I.

(A) Effect of ERT in MPS I patients without anti-IDUA antibodies. In the LSD MPS I, deficiency in the enzyme IDUA results in the accumulation of GAGs within lysosomes in patient cells. ERT involves i.v. injection of M6P-modified IDUA that can diffuse to cells and bind to the M6P receptor (M6PR) on the cell surface. M6PR can be internalized with the IDUA and translocate the enzyme to the lysosome, resulting in GAG degradation and a reduction in lysosome size. M6PR can then be recycled to the cell surface or replaced with new receptor. (B) Effect of ERT in patients with anti-IDUA antibodies. In some MPS I patients, a significant immune response to ERT has been shown; however, little was known about the effect of anti-enzyme antibodies on treatment outcome. In this issue of the JCI, Dickson et al. (2) show that in dogs with MPS I receiving IDUA via ERT, anti-IDUA antibodies may develop and bind to IDUA and sterically block MP6 from binding M6PR. This results in a failure of the enzyme to reach the lysosome and lack of a therapeutic effect. The authors go on to demonstrate that the induction of IDUA-specific immune tolerance in these animals, compared with dogs that were not tolerized to IDUA, improved IDUA uptake, increased GAG degradation, and reduced tissue pathology. Therefore, transient immunosuppression may enhance ERT for LSDs.