Long-term intravenous treatment of Pompe disease with recombinant human alpha-glucosidase from milk.

Abstract

Objective. Recent reports warn that the worldwide cell culture capacity is insufficient to fulfill the increasing demand for human protein drugs. Produc- tion in milk of transgenic animals is an attractive alter- native. Kilogram quantities of product per year can be obtained at relatively low costs, even in small animals such as rabbits. We tested the long-term safety and effi- cacy of recombinant human -glucosidase (rhAGLU) from rabbit milk for the treatment of the lysosomal stor- age disorder Pompe disease. The disease occurs with an estimated frequency of 1 in 40 000 and is designated as orphan disease. The classic infantile form leads to death at a median age of 6 to 8 months and is diagnosed by absence of -glucosidase activity and presence of fully deleterious mutations in the -glucosidase gene. Cardiac hypertrophy is characteristically present. Loss of muscle strength prevents infants from achieving developmental milestones such as sitting, standing, and walking. Milder forms of the disease are associated with less severe mu- tations and partial deficiency of -glucosidase. Methods. In the beginning of 1999, 4 critically ill pa- tients with infantile Pompe disease (2.5- 8 months of age) were enrolled in a single-center open-label study and treated intravenously with rhAGLU in a dose of 15 to 40 mg/kg/week. Results. Genotypes of patients were consistent with the most severe form of Pompe disease. Additional mo- lecular analysis failed to detect processed forms of -glu- cosidase (95, 76, and 70 kDa) in 3 of the 4 patients and revealed only a trace amount of the 95-kDa biosynthetic intermediate form in the fourth (patient 1). With the more sensitive detection method, 35S-methionine incorpora-