Rationale for Enzyme Therapy in MPS I

The rationale of ERT was proposed as a concept by Hers in 1964 [27], but was first practically developed for Gaucher's disease after more than 20 years of effort from the laboratory of Roscoe Brady and colleagues [28]. His group showed that a modified form of purified placental glucocerebrosidase (Ceredase®, alglucerase for injection) could be administered to human Gaucher patients and successfully reduce the organomegaly, anemia, and thrombocytopenia associated with that disorder [see Chapter 6]. The placental form was targeted to the mannose receptor by sequential deglycosylation, leaving the high-mannose core oligosaccharides that were shown to enhance targeting to macrophages, the cell type with the most storage in Gaucher patients. The basic concepts of enzyme infusion and carbohydrate receptor-mediated uptake, as well as the commercial success of Ceredase and the recombinant version Cerezyme® (imiglucerase for injection), provided an important model and rationale for treating MPS I. In contrast to Ceredase, treatment of MPS I required the development of recombinant enzyme sources, and a-L-iduronidase required targeting and uptake into a broader array of tissue types via the M6PR.

Based on the success with Ceredase and the early work of Neufeld and coworkers demonstrating in vitro uptake and correction, the possibility of enzyme therapy for MPS existed. Following the cloning of the cDNA for the enzyme, recombinant production was possible and was developed. Although early preclinical studies in the canine model of MPS I showed early success, it became more difficult for the work to receive investment from industry. In 1997, BioMarin Pharmaceutical Inc. first decided to invest in the development of what would become Aldurazyme. Later, in September 1998, Genzyme Corporation joined BioMarin in codeveloping Aldurazyme as part of a 50:50 joint venture.

Was this article helpful?

0 0

Post a comment