Medication Summary
Treatment for this fatal disorder is limited. [12, 18] A copious amount of research into acid maltase deficiency (AMD) is exploring the possibility of replacing the deficient enzyme by means of gene therapy. [13] Up to this point, the results have been frustratingly unfruitful. Future strategies may include in-vivo or ex-vivo gene therapy and/or mesenchymal stem cell or bone marrow transplantation approaches. Some results have been positive in animal models, but to extrapolate these results to the human form, new approaches to AMD must be determined and improvements in the access to cardiac and skeletal muscle must be made. Newer, more efficacious and innocuous vectors also must be discovered. L-alanine supplementation in late-onset AMD has been shown to decrease resting energy expenditure.
Emerging research has shown that infusions of recombinant human alpha-glucosidase from rabbit milk is helpful for stabilizing pulmonary function and improving muscle fatigue in early onset and late-onset Pompe disease. [19, 20] The younger and least affected children have shown the most improvement and delay in the progression of the disease process.
Originally described in the treatment of mice with glycogen storage disease, Ven den Hout et al, in an open-label study, treated 4 babies with recombinant human alpha-glucosidase obtained from rabbit milk. [21] Recombinant glucosidase was administered intravenously at a weekly dose of 15-20 mg/kg and later was increased to 40 mg/kg. Alpha-glucosidase activity normalized in muscle, the tissue morphology and motor and cardiac function improved, and the left ventricular mass index significantly decreased. Normal neurologic development was noted in all patients. Subsequent studies have involved the use of recombinant human alpha-glucosidase derived from Chinese hamster ovary cells. [3, 22]
In a 2009 open-label, multicenter study, Nicolino et al employed intravenous treatment with recombinant human alpha-glucosidase in 21 patients, aged 3-43 months, with advanced Pompe disease. [19] The drug was administered every 2 weeks for up to 168 weeks; the investigators found that, compared with an untreated reference cohort, the risk of death in the treated children was reduced by 79% (P < 0.001), and the risk that invasive ventilation would be required was decreased by 58% (P = 0.02).
A prospective cohort study by Kuperus et al reported that in adults with AMD, long-term enzyme replacement therapy has a beneficial impact on muscle strength, pulmonary function, and levels of daily life activity. The study had a median 6.1-year follow-up period, which included 5 years of enzyme replacement therapy, with the treatment having its greatest effect during approximately the first 2-3 years. [23]
Similarly, a study by Semplicini et al indicated that in adult AMD, improvements in walking ability and, probably, stabilization of respiratory function result from enzyme replacement therapy with alglucosidase alfa. Initially, treated patients showed a significant increase of 1.4% per year in the 6-minute walk test, with a subsequent decrease of 2.3% per year (cutoff point at 2.2 years). In addition, the motor function measure score improved by 6.6% per year, with a subsequent reduction of 1.1% per year after 0.5 years. Moreover, the maximum expiratory pressure remained stable throughout the follow-up period. The study’s results, according to the investigators, indicated a ceiling effect for the 6-minute walk test in the first 3 years for patients who undergo enzyme replacement therapy. [24]
The lessons learned from research into AMD may lead to better understanding and treatment of other genetic disorders. [25]
Enzyme replacement
Class Summary
Used as replacement therapy. Recombinant human enzyme alpha-glucosidase has recently been designated an orphan drug. [26]
Previously, although the form of alglucosidase alfa known as Myozyme had been approved by the US Food and Drug Administration (FDA) for use in the treatment of patients younger than 8 years with infantile acid maltase deficiency (Pompe disease), the form known as Lumizyme had been approved only for patients with late-onset acid maltase deficiency who were aged 8 years or older. In 2014, however, the FDA also approved Lumizyme for patients younger than 8 years. [27]
Alglucosidase alfa (Myozyme)
Recombinant human enzyme alpha-glucosidase (rhGAA) indicated as an orphan drug for treatment of Pompe disease. Replaces rhGAA, which is deficient or lacking in persons with Pompe disease. Alpha-glucosidase is essential for normal muscle development and function. Binds to mannose-6-phosphate receptors and then is transported into lysosomes; undergoes proteolytic cleavage that results in increased enzymatic activity and ability to cleave glycogen. Improves infant survival without requiring invasive ventilatory support compared with historical controls without treatment.
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Glycogen molecule; by cleaving glycogen's 1,4 and 1,6 alpha-glycosidic linkages, the enzyme acid maltase gives rise to free glucose molecules.
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Metabolic pathways of carbohydrates.
