Dr David Ayares, VP of Research and Development
PPL Therapeutics Inc.
Telephone: 540 961 5559

Blacksburg, VA PPL Therapeutics Inc is pleased to announce that on 5^th March 2000, five piglets, all healthy, were born as a result of nuclear transfer (cloning) using adult cells. This is the first time cloned pigs have been successfully produced from adult cells. DNA from blood samples taken from the piglets was shown in independent tests to be identical to DNA from the cells used to produce the piglets but clearly different from DNA taken from the surrogate mother. The DNA tests were carried out by Celera-AgGEN on coded samples. The cell samples had been provided to the testing company before the piglets were born.

The successful cloning of these pigs is a major step in achieving PPL’s xenograft objectives. It opens the door to making modified pigs whose organs and cells can be successfully transplanted into humans; the only near term solution to solving the worldwide organ shortage crisis. Pigs are the preferred species for xenotransplantation on scientific and ethical grounds. Clinical trials could start in as little as four years and analysts believe the market could be worth $6 billion for solid organs alone, with as much again possible from cellular therapies, eg. transplantable cells that produce insulin for treatment of diabetes.

Nuclear transfer in pigs has proved to be more difficult than for other livestock, in part because pig reproductive biology is inherently more intractable, and partly because pigs need a minimum number of viable fetuses to maintain pregnancy, whereas sheep and cows, for example, need only one.

The method used to produce the five female piglets, to be named Millie, Christa, Alexis, Carrel and Dotcom, was different from that used to produce "Dolly" in that it used additional inventive steps for which a patent application has been filed. The work was carried out by PPL’s US staff in Blacksburg, Virginia, partly supported by an ATP Award from the US Government’s National Institute of Standards and Technology. This award has as its objective the production of a "knock-out" pig, i.e. a pig which has a specific gene inactivated. The ability to clone pigs is the first essential step in achieving this objective.

The gene to be inactivated is alpha 1-3 gal transferase. This gene is responsible for adding to pig cells a particular sugar group recognized by the human immune system as foreign and which therefore triggers an immune response leading to hyperacute rejection in humans of the transplanted organ. PPL has already achieved the required targeted gene knock out in pig cells, using the same patented technology that led to the lambs Cupid and Diana.

"In continuing its proud tradition of achieving world firsts – first to clone an adult mammal, Dolly (with the Roslin Institute), first to achieve gene knock-out in livestock, and now first to clone pigs – PPL has built up the technical expertise and intellectual property to be the first to produce the type of pig which should become the industry standard for xenotransplantation – a pig lacking the alpha 1-3 gal transferase gene."

"We are delighted. Earlier ultrasonic scans suggested we might have three or possibly four developing fetuses. The fifth was a bit of a surprise but it is easy in pigs for a fetus to hide beneath another during ultrasound scans. Solving nuclear transfer in pigs was quite a challenge, so our ultimate success was all the more rewarding. This was a great team effort by all at PPL."

In addition to today’s announcement, PPL’s xenograft program has already made considerable progress in that potential solutions for all the four known causes of xenograft rejection have been devised and shown to work in cell based experiments. In addition to the gene knock-out discussed above that is required to prevent hyperacute rejection, three more genes will need to be introduced into pigs or into pig cells to control the two causes of delayed xenograft rejection. Finally, potential transplant patients will be given a transfusion containing modified cells, taken from the carefully selected strain of pigs that will supply the organs, which will "tolerize" the patient and thereby reduce long term rejection.

"We are unaware of any other group that has as comprehensive an approach to xenotransplantation as PPL. All the known technical hurdles have been overcome. It is now a case of combining the various strategies into one male and one female pig, and breeding from these."

"An end to the chronic organ shortage is now in sight. The next step for PPL is to repeat the pig cloning experiment to produce knock-out pigs. We are looking at various ways to fund our xenograft program, including discussions with potential marketing partners."

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 Notes to Editors

1. Xenotransplantation is the transfer of organs from one species to another. The fundamental problem with transferring organs between species is rejection by the recipient’s immune system. PPL’s program aims to overcome the causes of rejection and allow the development of a stock of transgenic animals containing genetic modifications which can be used as organ donors for humans.
2. For additional information on Xenotransplantation please visit PPL’s web site: www.ppl-therapeutics.com/bkgroundinfo/pigs
3. PPL Therapeutics is a biopharmaceutical company which is one of the world’s leaders in the application of transgenic animal technologies to the development and production of human proteins for therapeutic and nutritional applications. PPL’s three lead products are AAT, fibrinogen and bile salt stimulated lipase (BSSL). PPL is the only company to offer a wide range of animals for transgenic protein production, including sheep, cows, rabbits and pigs.
4. PPL has a broad pipeline of diverse protein products including AAT, the Company’s lead product, which is currently in Phase II clinical trials for cystic fibrosis. AAT is also under development for the treatment of congenital deficiency. PPL’s other lead products are fibrinogen and bile salt stimulated lipase (BSSL).
5. PPL has a world wide exclusive licence from the Roslin Institute to use the Institute’s intellectual property relating to nuclear transfer (cloning) in the field of production of proteins for pharmaceutical and nutraceutical use in the milk of ruminant livestock and rabbits.
6. It had long been decided that the first cloned pig PPL produced in the new millennium would be called Millie. Christa, Alexis and Carrel are named after Dr Christian Barnard, who performed the first human-human heart transplant in 1967, and Dr Alexis Carrel, Nobel prize winner in 1912, for his significant work in the field of transplantation. The unexpected fifth is called Dotcom, or Dotty for short, because as Ron James joked: "Any association with dotcoms right now seems to have a very positive influence on a company’s valuation."