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