Cloned animals offer firms fast path to new drugs

Leaving aside the science fiction scenarios and ethical debates, the first products to emerge from the remarkable cloning of an adult sheep by British researchers will probably be animals that can serve as drug factories.

PPL Therapeutics PLC, a small biotechnology company based in Edinburgh, Scotland, has the rights to the technology developed at the Roslin Institute for the production of genetically altered mammals that could produce therapeutic proteins in their milk. Patents have been applied for. The institute retains all agricultural rights.

Although the Roslin Institute's lamb is ordinary in every respect but its conception, scientists could easily clone animals genetically engineered to produce pharmacologically useful proteins in their milk, Dr. Ron James, managing director of PPL, said. This would be more efficient than the current process of cultivating genetically altered yeast, bacteria or mammalian cells. PPL already uses genetically altered, or transgenic, animals to produce drugs, as does the Genzyme Transgenics unit of Genzyme Corp., based in Framingham, Mass. But in both cases, the gene that will prompt production of the protein is added to cells at an early stage of development. Only some cells take up the genes and produce the protein efficiently, so the results, both in terms of the animals produced and the amount of protein from each animal, are inconsistent. By current methods, "to get a transgenic animal, you have to try and try and try, and it's a probability game," said Viren Mehta, a biotechnology analyst with Mehta & Isaly. "Here, if you succeed in making that transgenic cloned sheep, you are essentially home free. You just keep making them." But James said the cloning of the sheep was "repeatable, reproducible science." He said the company and its collaborators at the Roslin Institute had already cloned seven sheep, including three different breeds from three different cell types, although just one of these was from an adult cell. The technology is equally applicable to pigs, goats, rabbits, indeed any mammal. James said the company could produce transgenic cloned animals capable of secreting pharmacologically useful proteins in their milk within two years. These will give more consistent levels of protein than do current transgenic animals, he said. "Also, instead of producing just one, we could produce half a dozen females at a time, making sure we could produce enough proteins to go into clinical trials," he said. Drugs from these trials, if successful, would be about a decade away. PPL has about 120 employees in Edinburgh, with 20 at its American subsidiary, PPL Therapeutics, in Blacksburg, Va., and 5 in New Zealand. A PPL drug produced by transgenic sheep, an alpha-1 antitrypsin protein inhibits the enzyme elastase, is in the first phase of human clinical trials for treating cystic fibrosis. Phase one trials demonstrate safety of a new drug; efficacy and dosing are established in the second and third phases. In October, Genzyme completed phase one trials of its first transgenically derived drug, antithrombin 3, a protein involved in the blood-clotting process that is normally derived from plasma but that the company produced in the milk of genetically altered goats. Genzyme said safety was demonstrated in healthy patients who were given clinical dosages well above those expected to show efficacy. The market for the drug is about $200 million a year. Transgenically derived proteins should be safer than blood-derived products, because they will not be subject to the theoretical risk of transmission of viruses, including HIV and hepatitis. They should also be less costly than biotechnology drugs produced by fermentation because one large mammal can produce far more protein in her milk than the vast colonies of cells needed for current processes. Biotechnology industry analysts say these could substantially increase the market for therapeutic proteins, currently about $7.6 billion dollars a year, and expected to grow to $18.5 billion dollars by 2000. The ability to clone adult mammals could encourage the production of transgenic animals with organs suitable for transplants to humans, a possible solution to the chronic shortage of organs. Four small biotechnology companies are racing to develop pigs that may serve as organ donors for humans. Such cross-species operations could be common in a decade, the companies say.

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