S2.2 Enzyme replacement therapy in the infantile-onset Pompe disease

Until the end of the last century the management of Pompe disease (PD) was exclusively based on multidisciplinary interventions aimed at providing support therapies to patients. Enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA, Myozyme) was introduced in 2000 and is presently the only approved pharmacological treatment for PD. rh- GAA is administered periodically to patients by an intravenous route, and is internalized by cells and target tissues through the mannose-6-phosphate receptor pathway. The first clinical study on ERT in PD was conducted in four Dutch patients affected by the infantile form of the disease (1) that were treated for 36 weeks with an enzyme preparation derived from transgenic rabbit milk. Both the results of this trial and those of a long-term follow-up study (2) supported the efficacy of ERT on cardiac involvement, motor activity, and patients' survival. Since then a number of reports of almost a hundred patients treated with rhGAA, mostly with the classical infantile-onset PD, were published in the literature. Recently formal studies on the efficacy of ERT in PD were performed also in patients with the juvenile/adult forms of the disease (3, 4). An international PD registry has become active since 2004, and will likely add further information on long-term efficacy of ERT. Like for other lysosomal storage diseases ERT in PD showed important success together with some limitations. Specifically, excellent results were obtained in terms of functional correction of cardiac disease and of glycogen clearance in liver. On the other hand it became evident that correction of skeletal muscle pathology is a difficult challenge and that not all patients respond equally to ERT (5). Several factors appear to affect the efficacy of ERT and the outcome of PD patients, including age at the start of treatment, stage of skeletal muscle damage, antibody responses, insufficient targeting of rhGAA to skeletal muscle and high clearance of the enzyme by the liver. It was a common experience of physicians involved in the care of PD patients that the earlier was start of treatment, the better would be the outcome. This concept was formally proven by recent studies done in Taiwan, where a large-scale newborn screening pilot program was performed during the past few years (6). The results from this study clearly indicated that in patients identified by the neonatal screening and treated earlier than historical patients showed improved outcome in terms of motor activity and ventilatory-free survival. The immune status of PD patients has emerged as another important factor that impacts ERT efficacy. In a recent study the effects of ERT in 11 cross-reactive immunological material (CRIM) negative patients were compared with those obtained in 21 CRIM positive patients (7). CRIM-positive patients showed lower antibody titers, and a better response to ERT, while CRIMnegative patients showed an attenuated response to enzyme with significantly decreased survival, invasive ventilation-free survival, less improvement in cardiac response, and regression of motor milestones. Other studies implicated cellular abnormalities triggered by glycogen storage as additional factors affecting ERT efficacy. Cardone et al. (8) demonstrated an abnormal recycling of the cation-independent mannose-6-phosphate receptor (CI-MPR) in cultured PD fibroblasts. As the integrity of the CI-MPR pathway is essential for efficient uptake and lysosomal delivery of recombinant enzymes used for ERT, the abnormal trafficking of the receptor in PD fibroblasts resulted in an impaired correction of enzyme activity by rhGAA. The abnormalities of CI-MPR trafficking were more prominent in fibroblasts from severe and intermediate PD patients, apparently correlating with disease severity. Raben et al. (9) demonstrated that abnormalities of autophagy also impact on ERT efficacy and that suppression of autophagy in combination with ERT resulted in a near-complete glycogen clearance and restoration of skeletal muscle architecture in a mouse model of PD. The limitations of ERT efficacy point to the need for improved therapeutic strategies such as immune modulation, early start of ERT, pharmacological chaperone therapy (10) and its combination with ERT (11), substrate reduction (12). Gene therapy is currently under investigation as an alternative therapeutic option for the treatment of PD patients.