Immune modulation in Pompe disease treated with enzyme replacement therapy.

Pompe disease is a lysosomal storage disease characterized by massive glycogen deposition in skeletal, cardiac and smooth muscle secondary to the deficiency of acid α-glucosidase (GAA) [1]. Once rapidly fatal, it has become a treatable condition since the development of enzyme replacement therapy (ERT) with alglucosidase α (recombinant human GAA [rhGAA], Myozyme/Lumizyme Genzyme Corp. Cambridge, MA, USA) [1]. However, while this treatment has proven to be efficacious in both infantile and late-onset Pompe patients [2,3], many challenges remain. The development of an immune response with resultant loss of therapeutic efficacy of ERT remains a significant issue in Pompe disease, most notably in the infantile form. Similar obstacles have been faced in other conditions treated with therapeutic proteins, including hemophilia, diabetes and multiple sclerosis, as well as lysosomal storage diseases like Fabry disease, Gaucher disease and the mucopolysaccharidoses [4,5]. In addition to the human burden, hundreds of millions of dollars are wasted in the use of therapeutic proteins in patients who are not responding to the treatment because of antibodies developed against them [6]. Therefore, the identification of patients at risk of developing an immune response and the investigation of novel immuno modulatory strategies to preclude or reverse immune responses and to induce immune tolerance is of paramount importance, not only for improving the functional status of individual patients, but also for minimizing wasteful financial expenditures. The development of high, sustained antirhGAA IgG antibody titers is associated with decreased overall and ventilator-free survival and diminished cardiac and motor outcomes in infantile Pompe disease (IPD) treated with ERT [7–9]. Earlier studies in Pompe disease treated with ERT have demonstrated that the cross-reactive immunologic material (CRIM) status can be used to predict treatment response, with CRIM-negative status portending the development of high, sustained antibody titers and poor treatment outcomes [7,8]. However, later work in IPD revealed that a subset of CRIM-positive patients may also develop high, sustained antibody titers and correspondingly poor treatment outcomes [9]. Recently, the development of high antibody titers that adversely impact treatment outcomes has been noted in late-onset Pompe disease as well [10,11]. Similar challenges have been faced in the murine Pompe model, in which ERT administration is complicated by antibody formation and infusion-associated reactions. This murine Pompe model is analogous to the CRIM-negative patients in that there is a complete absence of endogenous GAA, prompting the immune system to mount a robust immune response to exogenous enzyme. Preclinical work in this model prevented an increase in antirhGAA antibody titers in the ERT-naive setting with the use of methotrexate, while response to mycophenolate and cyclosporin A/azathioprine was variable. This protocol Immune modulation in Pompe disease treated with enzyme replacement therapy