Multicellular living organisms and unmodified parts thereof and – Nonhuman animal – Transgenic nonhuman animal
Reexamination Certificate
1994-11-21
2002-12-17
Crouch, Deborah (Department: 1632)
Multicellular living organisms and unmodified parts thereof and
Nonhuman animal
Transgenic nonhuman animal
C800S018000, C800S025000, C435S325000
Reexamination Certificate
active
06495735
ABSTRACT:
This invention relates to biologically compatible material for use in transplants, and to the production and use of such material.
The replacement of failed or faulty animal (particularly human) tissue, including organs, has over the last four decades become a common place therapy in clinical medicine. These replacement therapies range for example from the use of the polyethylene terephthalate sold under the trade mark DACRON by DuPont to repair faulty blood vessels to the use of saphenous vein as an autograft to by-pass blocked arteries and to the transplantation from one human to another of a heart.
Organ transplantation has undergone significant development with modern immunosuppressants allowing high success rates to be achieved at relatively modest cost. The demand for organ transplantation has increased rapidly. There are now more than 20,000 organ transplants per annum carried out worldwide. This, however, represents only approximately 15% of the need as assessed by current criteria. The supply/demand ratio of donor organs of all types can not be met from existing sources. This is perhaps best illustrated with the demand for heart transplantation. The first heart transplantation by Barnard in 1967 generated considerable press coverage. Within a year, 101 heart transplants had been performed in 22 countries by 64 different surgical teams. Disillusionment followed the poor results obtained so that by the early 1970s fewer than 30 transplants per year were being performed worldwide. The introduction of cyclosporin immuno-suppression, however, has revolutionarised heart transplantation so that most centres can now anticipate success rates for heart transplantation of more than 80% one year graft (and patient survival). As expertise is gained, this survival rate can reasonably be expected to increase further. The success of this procedure, of course, fuels demand so that the medical profession and the general public become more aware that heart transplantation offers a real alternative to death, so more and more patients are referred for the procedure. Currently, over 2,000 heart transplants per annum are performed.
Today, the greatest risk of death in heart transplantation is while waiting for a suitable donor organ to become available. While the artificial heart offers a short-term support device for these patients, long-term demands are for more heart transplant centres and a greater donor supply. The potential number of individuals who might benefit from cardiac transplantation has never been scientifically established, but published estimates of the need for heart transplantation have ranged widely between 50 and 250 people per million per year depending on selection criteria, age of recipient, disease and so forth. Whatever the actual figure may be, it is quite clear already that current donor supply options are incapable of meeting demand. Similar comments can be made for kidney and liver transplantation, and it seems likely that once pancreas or Islet of Langerhans cell transplantation becomes a widely-accepted therapeutic procedure for the treatment of diabetes, shortage of this tissue will also become a prime concern.
There are further disadvantages with current transplantation therapy. It is by no means always the case that donor organs are fit for use in transplantation, not least because many organ donors are themselves victims of some accident (for example, a road accident) which has caused death by injury to some organ other than that which is being transplanted; however, there may be some additional injury to or associated difficulty with the organ to be transplanted.
Further, because of the unpredictable availability of organs from donors, transplant surgery often can not be scheduled as a routine operation involving theatre time booked some while in advance. All too frequently, surgical teams and hospital administrators have to react the moment a donor organ is identified and work unsocial hours, thereby adding to administrative and personal difficulties.
In the case of heart, liver and lung transplants, if rejection is encountered it will not usually be possible to retransplant unless by chance another suitable donor becomes available within a short space of time.
Apart from the above medical difficulties, current transplantation practice can in some cases involve social difficulties. In the first place, there may be religious objections to removing organs from potential donors, particularly in cultures believing in reincarnation. There are of course other ethical and social difficulties encountered in removing organs from dead humans, particularly as consent is required in some countries. Finally, the appearance of a commercial trade in live kidney donors is causing concern, particularly in certain third world countries, and it would be socially desirable to suppress or reduce such a trade.
Conventional transplantation surgery, as outlined above with its disadvantages, involves the transplantation from one animal of a particular species (generally human) to another of the same species. Such transplantations are termed allografts. Because of the difficulties with conventional allograft supply, as outlined above, attention has focused on the possibility of using xenografts in transplantation. Xenografting is the generic term commonly used for the implantation of tissues, including cells and organs, across species barriers.
There have already been several examples of the successful use of xenografts in therapeutic replacement schedules. For example, recent years have witnessed the use of pig tissue for aortic valve replacement, pig skin to cover patients with severe burns, and cow umbilical vein as a replacement vein graft. All of these xenografts have, however, one point in common: they provide a mechanical replacement only. The tissue used is biologically non-functional. The reason for this is that the immune processes existing in man immediately (within minutes or hours) destroy the cellular integrity of tissues from most species. Such xenografts are known as discordant xenografts.
The ferocity of this destruction is phylogenetically associated. Thus, tissue from the chimpanzee, which is a primate closely related to man, can survive in man in much the same way as an allograft; such a xenograft is known as a concordant xenograft.
While it may be thought that concordant xenografts might provide the answer to the difficulties with allografts, in practice this is probably not the case. Chimpanzees are much smaller than man and chimpanzee organs are generally not big enough to work in man. In the case of kidneys this may be overcome by transplanting two chimpanzee kidneys to replace a failed human kidneys, but for liver and heart this is clearly not a possibility. Furthermore, chimpanzees breed slowly in nature and poorly in captivity, and the demand for chimpanzees as experimental animals (particularly in the current era of research into Acquired Immune Deficiency Syndrome (AIDS)) means that, yet again, demand is outstripping supply. Additionally, there may be some social difficulty with the public acceptance of the use of other primates as xenograft donors.
Attention has therefore refocused on discordant xenografts. It has been commonly believed that the reason why discordant xenografts fail so rapidly, is the existence in the recipient species of “naturally occurring” antibodies against as yet undefined antigens of the donor species (Shons et al (
Europ. Surg. Res
. 5 26-36 (1973)). The antibodies are called “naturally occurring” because they are found to exist in individuals who have not had any immunological challenge from the donor species.
The rapid rejection—known as hyperacute antibody-mediated rejection—of an organ graft is well documented. In the early 1960s, when (allograft) kidney transplantation became a routine treatment, it was observed that transplanted kidneys were occasionally rejected by the recipient whilst the operation was still in progress. During a transplant operation, the kidney will as a rule become red and firm in consistency soon
White David James
Williams Alan Frederick
Crouch Deborah
Furman Diane E.
Pfeiffer Hesna J.
Savitsky Thomas R.
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