Transgenic Animals as Bioproducers of Therapeutic Proteins

Abstract

Many human therapeutic proteins are currently produced with the aid of recombinant DNA technology in microbial bioreactors and a few also in large-scale animal cell cultures. Although extremely cost-efficient, the microbial production system has many inherent limitations. Micro-organisms, such as bacteria, can read the universal genetic code and hence produce human proteins with correct amino acid sequence, but cannot carry out post-translational modifications, such as glycosylation, or fold the newly synthesized protein properly to ultimately generate a biologically active entity. Moreover, even though the production of the proteins as such is inexpensive, the downstream processing of the final product may be extremely difficult and costly. Many of these disadvantages, especially the lack of post-translational modifications, can be overcome by employing large-scale animal cell cultures for the production of proteins of pharmaceutical interest. However, due to the long generation time and the requirement for rich culture media, the use of animal cell bioreactors is unacceptably expensive. With the advent of transgenic technology, the production of human pharmaceuticals in large transgenic animals has become more and more attractive. The use of targeted gene transfer, the expression of the transgene of interest can be directed to occur in the mammary gland of large farm animals, such as pigs, sheep, goats or dairy cattle, and hence the transgene product is ultimately being secreted into the milk. Although not yet in commercial use, the last few years have witnessed a remarkable progress in this area and proved the feasibility of the use of 'molecular farming' in high-quantity, low-cost production of valuable therapeutic or industrial proteins. While reviewing the progress of the field over the past few years, we discuss in somewhat greater detail aspects connected with the use of dairy cattle as bioproducers of human therapeutic proteins.