Our goal is to develop transgenic tobacco for the bioproduction of a cost-effective human glucoceribrosidase (hGCase) therapeutic. Replacement therapy using hGCase purified from human placenta has proved effective in the treatment of Gaucher's disease. However, this source is in such short supply and so costly that current research and treatment programs are being severely hindered. In phase I we successfully demonstrated the feasibility of this project by introducing a human gene encoding hGCase into tobacco cells and regenerating transformed plants expressing high levels of enzymatically functional hGCase. The goal of phase II is to successfully address the major remaining technological problems required to move this product to phase II scale-up for research and therapeutic testing. Specific objectives of phase II are to 1) Characterize the hGCase produced in tobacco with respect to post- translational modifications, activity, and kinetic parameters, 2) Test the effects of varying expression levels, targeting sequences and subcellular localization on hGCase accumulation, activity, stability and processing, 3) Develop strategies for modifying hGCase glycans to enhance therapeutic utility. Plant production of bulk quantities of lower cost hGCase would provide an attractive alternative to current commercially available therapeutic products for Gaucher's disease.
Current patient cost of enzyme therapy for Gaucher's averages over $150,000 per year. The enormous expense of this drug is caused by limited supplies of placenta and high costs for manufacturing glucoceribrosidase (hGCase). Plant based production of hGCase could provide bulk quantities of a highly competitive therapeutic product at substantially lower per patient costs.
| Cramer, C L; Weissenborn, D L; Oishi, K K et al. (1996) Bioproduction of human enzymes in transgenic tobacco. Ann N Y Acad Sci 792:62-71 |
