A global shortage of human organs for transplantation has lead to escalating waiting lists for life saving transplants of hearts, kidneys, livers and other organs. This has led the worldwide transplant community to review the options for organ procurement. Increasing the donation rate from humans has been calculated to have a relatively small impact on waiting lists while the availability of successful bioartificial organs is clearly still some way in the future. The use of animals as organ donors, or xenotransplantation, has been the subject of intense research and debate over the past two decades. Ethical considerations have led to the selection of the pig as the most likely source of organs for humans, although significant biological barriers exist to achieving long term organ survival and function in recipients. It is clear that some genetic manipulation of the donor pigs will be required to overcome these barriers.

Revivicor's announcement that it has produced five cloned piglets puts in place the final technical building block to enable it to produce pigs with organs which can be successfully transplanted into humans. Clinical trials could start in as little as two years and analysts believe the market could be worth $6 billion for solid organs alone, with as much again possible from cellular therapies, i.e. transplantable cells that produce insulin for treatment of diabetes.
Revivicor's interest in the development of transplantable pig organs stems from the fact that the available supply of human organs for transplant comes nowhere near to meeting the demand. In the US, for example, more than 62,000 patients are now waiting to receive donated hearts, lungs, livers, kidneys and pancreases. A new name is added to the list every 16 minutes and every day 11 people die waiting. Moreover, the US spends $30-$40 billion each year to care for people with end stage organ failure.

Although some people believe that if a change was made from an 'opt-in' donor card scheme to one where it was assumed organs could be used after death unless a person carried a card to say "no", this would solve the shortage, sadly, this is not the case. While it would undoubtedly help, demand would still far exceed the supply. This has been demonstrated in countries where such an opt-out system is operated. The reason for the continuing shortfall is that most people die of old age, cancer or heart disease, making their organs unusable.

In the future, so called "transgenic cloning", using human cells and understanding how to control the complex developmental events, may allow scientists to grow replacement organs in the laboratory, but even those involved in the work acknowledge that producing working organs, as opposed to specific cell types, is a long way off. Meanwhile, xeno organs offer the prospect of virtually unlimited supply and therefore transplantation early in the disease progression before consequential damage has been done to other parts of the body. If a xeno organ only lasted for example five years it would not be a problem because a new one could be supplied when required.

Revivicor is now in the best position worldwide to ultimately deliver a xeno organ that works, because we have developed, and filed patents for, a set of genetic modifications which we is believe will overcome each of the known sequential causes of xeno organ rejection. The science involved is impressive and the cloning of pigs contributes to overcoming one of the most important causes of rejection. This is the first hurdle that has to be overcome, so called hyperacute rejection, a reaction to the 'foreign' organ by the body's normal immune system.

To knock-out this gene, it was necessary to be able to do targeted gene modifications in pig cells and then to be able to produce a pig from these modified cells, and Revivicor has succeeded in producing these knock-out pigs. While the presence of the foreign sugar is by far the major signal for initiating an attack by the immune system, it is probably not the only one, so Revivicor will also add a gene to the pigs to produce a protein which naturally exists to moderate the action of the immune system. This gene addition strategy, combined with immune suppression drugs, has already been used with some success by other companies which have shown survival of pigs hearts in primates for several months.

Revivicor's combined approach of gene knockout plus immune response regulation should reduce the need for excessive amounts of immune suppression drugs which can themselves have long term undesirable side effects, and leave the body with limited defense to real invasions of foreign organisms such as harmful viruses.

During the four years it will take to get to trials in humans, a number of safety studies and safety systems will be put in place to minimize the possibility of introducing pig viruses into man. Already, the evidence collected by Novartis from some 160 worldwide patients given porcine cells, suggests that viral transmission will not easily occur.

Moreover, as more research is undertaken, it is likely that only a small number of the viral DNA sequences embedded in pig genes will be identified as essential to the formation of active virus. The pig cloning technology will provide the means by which these specific sequences could be deleted and the concern over infection by pig virus eliminated.