Developing efficient strategies for the generation of transgenic cattle which produce biopharmaceuticals in milk

At the close of the millennium, a revolution in the treatment of disease is taking shape due to the emergence of new therapies based on human recombin ant proteins. The ever-growing demand for such pharmaceutical proteins is a n important driving force for the development of safe and large-scale produ ction platforms. Since the efficacy of a human protein is generally depende nt on both its amino acid composition as well as various post-translational modifications, many recombinant human proteins can only be obtained in a b iologically active conformation when produced in mammalian cells. Hence, ma mmalian cell culture systems are often used for expression. However, this a pproach is generally known for limited production capacity and high costs. In contrast, the production of (human) recombinant proteins in milk of tran sgenic farm animals, particularly cattle, presents a safe alternative witho ut the constraint of limited protein output. Moreover, compared to cell cul ture, production in milk is very cost-effective. Although transgenic farm a nimal technology was still in its infancy a decade ago, today it is on the verge of fulfilling its potential of providing therapeutic proteins that ca n not be produced otherwise in sufficient quantities or at affordable cost. Since 1989, we have been at the forefront of this development, as illustra ted by the birth of Herman, the first transgenic bull. In this communicatio n, we will present an overview of approaches we have taken over the years t o generate transgenic founder animals and production herds. Our initial str ategies were based on microinjection; at the time the only viable option to generate transgenic cattle. Recently, we have adopted a more powerful appr oach founded on the application of nuclear transfer. As we will illustrate, this strategy presents a breakthrough in the overall efficiency of generat ing transgenic animals, product consistency, and time of product developmen t. (C) 1999 by Elsevier Science Inc.