Therapeutic Efficacy

Data from phase I/II clinical trials (recombinant enzyme produced by CHO cells treating infantile onset patients) indicate that cardiac muscle responds well to therapy, while skeletal muscle response is highly variable. Significant glycogen clearance and improvement of skeletal muscle function were observed only in a small number of patients [109]. Preclinical studies in a gene knockout mouse model of the disease also showed that CHO-cell-derived recombinant human a-glucosidase is much more effective in resolving the cardiomyopathy than the skeletal muscle myopathy. However, an additional preclinical study with the Japanese quail (a species of bird that can suffer from Pompe) showed that the CHO recombinant enzyme was also effective in reducing glycogen granules in skeletal muscle [110]. Recombinant enzyme from a transgenic rabbit has also been produced. An open-label study, consisting of four babies with Pompe disease treated with recombinant human a-glucosidase from rabbit milk at starting doses of 15 or 20 mg/kg, and later 40 mg/kg, was carried out. The enzyme was immunologically well tolerated. The transgenic enzyme and the CHO recombinant enzyme were both found to have similar therapeutic effects. Both clear glycogen efficiently from cardiac muscle but are less efficient on skeletal muscle [111]. The clinical trials have focused on the infantile onset form to date, but are to be extended to the adult onset form in future trials. The results of the trials to date have proven the current replacement therapy to be safe and effective.

Manipulation of the recombinant enzyme has been carried out in order to obtain more mannose-6-phospate ligands on the enzyme and therefore more efficient enzyme uptake, particularly into skeletal muscle tissues [112]. This form of the enzyme has had favorable results in the mouse model of the disease [97]. Other therapeutic avenues have also been explored, including gene therapy [113,114]. However, enzyme replacement therapy appears to hold the most promise for the near future.

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