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Enzyme replacement therapy

Pompe disease has long been an untreatable disorder, for which only supportive care was available. In March 2006 Myozyme, the first treatment for patients with Pompe disease, received marketing authorization in the European Union, followed in April 2006 by FDA approval in the United States. Myozyme is manufactured by Genzyme and is an 'enzyme replacement therapy' (ERT). The rationale for this therapy is to treat the disease by intravenous administration of the deficient enzyme.

The marketing approval of the first ERT for Pompe disease was the result of many years of research and development. During the development of the therapy, two methods using recombinant DNA technology have been explored: production of the enzyme in the milk of transgenic rabbits and production in Chinese Hamster Ovary cells (CHO-cells). The current product Myozyme is recombinant human acid α-glucosidase derived from CHO-cells. On this webpage a short overview is given of the clinical trials with the registered product and its predecessors.

Results of ERT in patients with infantile Pompe disease
The clinical safety and efficacy of recombinant human α-glucosidase derived from the milk of transgenic rabbits has been described for six patients with classic infantile Pompe disease. On a weekly dose of 40 mg/kg, all six patients survived well beyond 2 years of age, cardiac hypertrophy improved significantly, and those patients who were still in a relatively good clinical condition at baseline gained muscle strength and function. Alpha-glucosidase activity in muscle tissue reached normal limits for all but one patient. Muscle morphology improved in some patients, but not in all, depending on the degree of muscle pathology at start of treatment [1, 2]. One of the patients died at the age of 4 years.

The studies on ERT derived from CHO-cells show more or less similar results. The first published report on CHO-cell derived enzyme replacement therapy describes a trial which included three infants with Pompe disease, initially treated with 5 mg/kg recombinant human α-glucosidase twice weekly. Later on the two patients who did not respond so well were switched to a higher dose of 10 mg/kg 2-5 times per week. The primary endpoint was heart-failure free survival at one year of age, which was reached by all three patients [3]. In 2006 and 2007 the results from 2 other clinical trials were published. The first one included 8 infants with Pompe disease with an α-glucosidase activity of less than 1% of normal, cardiomyopathy, and hypotonia. After 52 weeks of treatment with a weekly dose of 10 mg/kg α-glucosidase, 6 patients were still alive, and 5 were free of invasive ventilator support. The cardiomyopathy had improved, as well as the growth and cognition of the patients. Five patients acquired new motor milestones; 3 walked independently. However, in the period following the initial study phase of 52 weeks, four of the patients died [4].

The other study included 18 infantile patients diagnosed before the age of 6 months, treated with recombinant human α-glucosidase at either 20 mg/kg (n = 9) or 40 mg/kg (n = 9) every other week. All patients survived to 18 months of age. It was calculated that treatment reduced the risk of death before the age of 18 months by 99%, reduced the risk of death or invasive ventilation by 92%, and reduced the risk of death or any type of ventilation by 88%, as compared to an untreated historical control group. The trial results did not show a clear advantage of the 40 mg/kg dose over the 20 mg/kg dose [5].

The results obtained so far thus show clear and significant effects of enzyme replacement therapy in infantile Pompe disease, including improvement of cardiomyopathy and prolongation of the lifespan. Nevertheless it should be realized that the therapeutic window in these patients is small and that patients may develop residual disease including contractures and respiratory insufficiency. To evaluate the full effects of the treatment, longer follow-up will be required.

Results of ERT in patients with late-onset Pompe disease
The results of ERT in late-onset Pompe disease have until now only been described for recombinant human α-glucosidase derived from the milk of transgenic rabbits. Three patients (two adolescents and one adult) initially received a weekly dose of 10 mg/kg, which was soon increased to 20 mg/kg/wk. Muscle strength and function of the patient who was least affected at start of treatment improved dramatically to normal levels. In the two severely affected patients muscle strength and function improved slightly, but they remained wheelchair-bound. Their pulmonary function stabilized, but they could not be weaned from the ventilator. However they reported less fatigue and increased quality of life [6].

Recently Erasmus MC participated in an open-label study on the safety and efficacy of Myozyme in 5 children aged 5-18 years and in a large randomized, double-blind, placebo-controlled clinical trial on the safety and efficacy of Myozyme in patients with late-onset Pompe disease. This trial included a total number of 90 patients from 7 centers worldwide. Further research on the long-term effects of enzyme therapy in children, adolescents and adults with Pompe disease is ongoing.

More information on Myozyme can be found on the Genzyme website.

Potential future treatments

Other therapeutic approaches are currently under development.  A short introduction is given below. 

Gene therapy
The rationale for gene therapy is to introduce the gene coding for the deficient enzyme into the somatic cells, thus creating a permanent enzyme source. To this end, the coding sequence for human acid α-glucosidase is inserted in a viral vector. For Pompe disease, gene therapy using adenoviral (Ad), adeno-associated (AAV) and hybrid Ad-AAV vectors has been investigated in rat, mice and quail. So far the results of gene therapy tests in animal models are promising, but sustained expression of the gene, prevention of antibody formation against the viral vector and/or α-glucosidase, and safety of the vector are still important issues to be addressed.

Chaperone therapy
Some of the pathogenic mutations in the acid α-glucosidase gene lead to forms of the enzyme that are poorly transported to the lysosome or are unstable in the lysosomal environment. The rationale for chaperone therapy is that certain small molecules may enhance the residual α-glucosidase activity in the lysosomes of patients with this type of mutations. The effect of chemical chaperones has so far only been tested in cultured fibroblasts from patients with Pompe disease [7]. 


  • Van den Hout H, Reuser AJ, Vulto AG, Loonen MC, Cromme-Dijkhuis A, Van der Ploeg AT. Recombinant human alpha-glucosidase from rabbit milk in Pompe patients. Lancet 2000; 356:397-398.
  • Klinge L, Straub V, Neudorf U, et al. Safety and efficacy of recombinant acid alpha-glucosidase (rhGAA) in patients with classical infantile Pompe disease: results of a phase II clinical trial. Neuromuscul Disord 2005; 15:24-31.
  • Amalfitano A, Bengur AR, Morse RP, et al. Recombinant human acid alpha-glucosidase enzyme therapy for infantile glycogen storage disease type II: results of a phase I/II clinical trial. Genet Med 2001; 3:132-138.
  • Kishnani PS, Nicolino M, Voit T, et al. Chinese hamster ovary cell-derived recombinant human acid alpha-glucosidase in infantile-onset Pompe disease. J Pediatr 2006; 149:89-97.
  • Kishnani PS, Corzo D, Nicolino M, et al. Recombinant human acid [alpha]-glucosidase: major clinical benefits in infantile-onset Pompe disease. Neurology 2007; 68:99-109.
  • Winkel LP, Van den Hout JM, Kamphoven JH, et al. Enzyme replacement therapy in late-onset Pompe's disease: a three-year follow-up. Ann Neurol 2004; 55:495-502.
  • Okumiya T, Kroos MA, Vliet LV, Takeuchi H, Van der Ploeg AT, Reuser AJ. Chemical chaperones improve transport and enhance stability of mutant alpha-glucosidases in glycogen storage disease type II. Mol Genet Metab 2007; 90:49-57.





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