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The w ork desc ribed in this rep ort ent itled XENOTRANSPLANTATION
has been carried out by Miss Trisha Ghosh under my supervision.
She is a bona fide stud ent o f MBA (Pha rm. Tec h), third yea r, Sc hoo l of
Pharma c y a nd Tec hnology Ma nage me nt, NMIMS University, Mumb ai.
Date: Ap ril 16th,2009 Guide:
Plac e:Mumba i Mrs. Reema Thomas,
Lecturer (Clinical Pharmacy)
Schoo l of Pharma cy & Tec hnolog y
Management
Sc hool of Pharmac y and Tec hnology Management,
SVKMs NMIMS University,
Vile-Parle, Mumbai-400056
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As required by university regulation, I wish to state that this work embodied in
this report titled XENOTRNSPLANTATION wa s Comp iled from va rious sources
und er the guida nc e of Mrs. Ree ma Thom as. This wo rk has not b ee n
submitted for any other degree of this or any other university. Whenever
references have been made to previous work of others, it has been clearly
indica ted as such and inc luded in the b ibliog raphy.
Miss Trisha Ghosh
Roll No.:20
Forwarded Through
Guide:
Dr. R. S. Gaud
Profe ssor Pha rmac eut ica l Sc ienc e,
Depa rtment of Pharmac eutic s,
Sc hoo l of Pharma c y and Tec hnologyManagement,
SVKM s, NMIMS University,
Vile Parle (W),
Mumbai 400056
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ACKNOWLEDGEMENTS
It is great pleasure for me to acknowledge all those who have contributed
towards the conception, origin and nurturing of this project.
With a deep sense of gratitude and the respect, I thank my esteemed research
guide Mrs. Reema Thomas , School Of Pharmacy and Technology Management,
Narsee Monjee Institute Of Management and Higher Studies), Mumbai for her
inestimable guidance, valuable suggestions and constant encouragement during the
course of this study. It is with affection and reverence that I acknowledge my
indebtness to her for outstanding dedication, often far beyond the call of duty.
I sincerely thank to Dr. R. S. Gaud , Dean, School Of Pharmacy andTechnology Management for allowing me to work on this project.
At this moment, I thanks with deep gratitude to my classmates andfriends for
their moral support, constant encouragement and patience absolutely needed to
complete my entire study. It was the blessing of them that gave me courage to face the
challenges and made my path easier.
I am indebted infinitely to care, support and trust being shown by my parents
without whom it would not be possible to complete this project.
(Trisha Ghosh)
Roll No. 20
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Contents :
Introduction 6
Disea ses treated by xenotransplantation 15
The need of xenotranspla ntation 17
The risks & hurdles invo lved in xenotransplantation 18
The potential use of allosensitized humans 25
Mod ifica tion of immunosupp ressive regimen 26
Xenotransplanta tion : cultura l, sp iritual, ethica l issues 27
The interest of animals 29
Is xenotransplanta tion intended to be permanent 32
Sc ientific resea rch c arried out in xeno transplanta tion 32
Xenotourism 33
Myths ab out xenotransplantation 35
Future d irec tions : genetic eng ineering 36
US FDA guid elines 37
Guidance to industry 41
Summary 44
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Introduction
Despite practical advances in transplantation medicine, the critical shortage of human
donor organs severely limits widespread clinical use. Developing alternative sources
of cells, organs, and implantable devices for replacement, regeneration, or mechanical
assistance of failing organs is, therefore, paramount. Rather than competing with each
other, these techniques can be complementary, with advances in one type jump-
starting progress in another. One technique can buy time while a patient awaits
application of another, or 2 or more techniques can be combined.
"To solve the transplantation crisis, we need to close the gap between the organ
shortage and the demand for organ substitutes, which will take a while," Robert M.
Nerem, PhD, of the Petit Institute for Bioengineering and Bioscience said at the
Georgia Institute of Technology in Atlanta. Although progress has been greater in
skin substitutes and orthopaedic applications, only replacement of vital organs can
lighten the heavy burden of chronic disease.
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What Is Xenotransplantation?
Xeno means strange, or foreign. The term xenotransplantation (pronounced zeeno-
transplantation) is used to describe a transplant between any two species of animals,
including humans.
Xenotransplantation is any procedure that involves the transplantation, implantation,
or infusion into a human recipient of either (a) live cells, tissues, or organs from a
nonhuman animal source, or (b) human body fluids, cells, tissues or organs that have
had ex vivo contact with live nonhuman animal cells, tissues or organs.i
When only cells are used, the material is often referred to as a cellular xenotransplant
or cellular xenograft. As well, there are certain kinds of xenotransplants which are not
true transplants at all, because the animal organ or cells stay outside the patients
body. These are called extra-corporeal (or outside-the-body) xenotransplants.ii
History:
Xenotransplantation is not a new concept. The idea of transplanting animal parts to
humans has always fascinated man. There are few non documented incidents during
very early
In the 1600s Russians had tried to cure fractures by replacing human bones with dog
bones,obviously unsuccessfully
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Later in the late 1800s frog skin is said to have been extensively used to treat skin
burns and ulcers. One British army surgeon is known to have used this procedure
successfully a plethora of times.
The first scientific reports on xenotransplantation , more specifically renal
heterotransplant appeared appeared early in this century.
In 1905 Princeteau inserted slices of rabbit kidney into nephrotomy on a child with
renal insufficiency. immediate results were excellent he wrote.. volume of urine
increased, vomiting stopped. On 16th
day the child died.
In 1910 Unger described his attempt at transplantation of kidneys from a non-human
primate into man. Patient died 32 hrs after transplantation & autopsy showed venous
thrombosis.
In 1923 Neuhof attemted treatment of a patient with mercury bichloride poisoning by
renal heteotranplant. Patient died 9 days later.
Scientific interest in transplantation died when neurological basis of rejection was
establishediii
.
In the early 1960s, renal xenotransplantation from chimpanzees and baboons to
humans was tried as was liver and cardiac xenografting. Preliminary studies
demonstrated the technical feasibility of the procedures. At that time, the ethics of
xenotransplantation was not questioned.iv
In 1984, after Bailey and associates transplanted the heart of a baboon into a
neonate
v
the ethical dilemma of xenotransplantation suddenly struck the medical
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community in the United States. At that time, there was some agreement that research
involving xenografts was ethically defensible because of the shortage of available
organs. However; the case of Baby Fae
vi
raised many ethical questions, notably those
concerning inadequate scientific preparation, the nature of consent for
xenotransplantation and the use of animals from an endangered species.
In the early 1990s, more powerful drugs for preventing rejection of a human organ
by a patients immune system were developed. These drugs provided hope that
xenotransplants might also be more successful. Several patients received animal
hearts or livers but did not survive more than 3 months.
In 1995 one patient in the United States received bone marrow from a baboon.
Although the baboon marrow was rejected by the patients body, the patient is still
alive and appears not to have any harmful side-effects from being treated with the
baboon bone marrow.
In the past few years there have been some encouraging results with cellular
xenotransplants.
In Sweden, 10 patients with diabetes received cells from the pancreas of pigs, to see if
these new cells would produce insulin. None of the pig cells produced insulin in the
long term, and none of the patients got sick from the transplanted pig cells.
In 1999, Maribeth Cook who was suffering from paralysis as an aftermath of stroke
was administered with 30 million fetal porcine cells by an injection to the brain. The
fetal porcine cells were used because they are functionally similar to the human fetal
cells. The procedure was successful and she is now able to walk.
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Currently, a clinical trial in the United States is transplanting specific brain cells from
fetal pigs into patients with Parkinsons disease. Early results indicate improvement in
some patients condition
vii
The different types of xenotransplantation:
When we hear about transplantation, we usually think of organ transplants such as
hearts or kidneys. However, it is important to stress from the outset the sheer variety
of ways of doing xenotransplantation.
Transplantation can also involve tissues, such as bone marrow, or clusters of
specialized cells, such as pancreatic islet cells (which produce insulin). These
transplants are called cell therapies.
Transplants can also involve different types of procedures. Most involve putting
living tissue, cells or an organ into a patient to replace diseased or failing parts of the
body. Less well known are external therapies, which occur outside the body of the
patient. An example is when blood from a patient with liver failure is passed through
a machine containing animal liver cells to remove toxic substances (a procedure
similar to kidney dialysis). Another external therapy involves growing human skin in
the laboratory over a layer of animal cells and later using the skin as a graft to treat
burnsviii
.
Some types of xenotransplantation are relatively advanced and close to moving
beyond research into treatment; others - particularly the transplant of whole organs -
are a long way from being used clinically.
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Some types aim to improve on current treatments, as with diabetes; others aim to
provide treatment where currently there is none, as in external therapies (mentioned
above).
Some types use cells, tissues or organs that are genetically modified; others do not.
Some types use relatively few animals or need not inflict great suffering; others use a
variety of animals, including primates, and may involve considerable suffering for
animals.
Some types use organs that are central to many people's sense of identity, such as
hearts or eyes; others involve parts that are likely to be less central, such as pancreatic
islet cells.ix
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Text description of image
The diagram illustrates th
first is animal cell therapie
transplanted into a human,
The second type of animal
cells from a pig's liver are
blood of a person who has
The third type of animal-t
ee different types of animal-to-human trans
, where insulin-producing cells from the pancr
o that the human can produce their own insuli
to-human transplantation is animal external t
ransferred into an external device, which is u
xperienced liver failure, and who is waiting fo
-human transplantation is animal organ trans
lantation. The
eas of a pig are
.
erapies, where
ed to clean the
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lants, where a
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whole organ (eg a kidney), is transplanted into a human to replace a failed kidney. The
patient thus experiences restored kidney function.
Clinical xenotransplantation
The current clinical experience with xenotransplantation is limited to 3 main areas:
tissue xenotransplantation, extracorporeal perfusion of a xenograft for the treatment of
fulminant liver failure and whole-organ xenotransplantation.
Tissue xenografting :
Tissue xenotransplantation with pig-to-human skin grafts and pig heart valve implants
has been used successfully for many years. Xenotransplantation using pig neural cells
has shown promise as a treatment for Parkinson's disease. Pancreatic islet
xenotransplantation offers the potential to cure insulin-dependent diabetes.
Transplanted islets are not initially vascularized: they become vascularized by
recipient vessels over time, thereby bypassing the hyperacute rejection seen in whole-
organ xenotransplantation. Pigs are a good source of donor islet tissue because
porcine and human insulin are structurally similar, pigs and humans have similar
glucose metabolism, and porcine insulin has been used for many years to treat
diabetes.
Xenoislet transplantation has been combined with allograft kidney transplantation in
patients with diabetes and end-stage diabetic nephropathy. Islet cell function was
demonstrated by porcine C peptide found in the urine in some patients; however,
insulin requirements were not affected by the xenotransplant. This work shows that it
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is possible to attain viable islet cells after xenotransplantation, but further
modifications are required to achieve clinical function that allows tapering or
withdrawal of insulin.
3
Extracorporeal perfusion with xenografts
Extracorporeal xenogeneic liver support has been used in patients with fulminant liver
failure as a temporary measure to allow time for the liver to recover function or for an
allograft to become available. A perfusion circuit is established that carries blood
from the patient through the hepatic artery and portal vein of the ex-vivo organ and
then returns the detoxified blood to the patient. Two of 5 patients described in the
recent literature were successfully managed by this technique until allotransplantation
could be performed.viii
Whole-organ xenografting :
There have been sporadic attempts at clinical whole-organ kidney, heart and liver
xenotransplantation.
In the early 1960s, Reemtsma and colleaguesiii
transplanted chimpanzee kidneys into
human recipients before dialysis was widely available. Some of these grafts had
adequate function early, but eventually all of the recipients succumbed to
uncontrollable rejection or infection.
In 1985, Bailey and associates transplanted a baboon heart into a newborn infant who
survived for 3 weeks until the graft was lost to antibody-mediated damage.
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In 1993, Starzl and colleagues
reported 2 cases of baboon-to-human liver
xenotransplantation in patients with end-stage liver disease secondary to chronic
active hepatitis B (1 patient was also HIV positive). Evidence of liver function
included normal coagulation profile, correction of hyperammonemia and clearance of
serum lactate; however, both patients had low serum albumin requiring repeated
transfusions. The first patient lived for 70 days, but the second patient died 26 days
postoperatively. Neither graft had evidence of rejection, and both of these patients
died from sepsis secondary to profound immunosuppression.
The use of a liver xenograft as a bridge to allotransplantation has been investigated.ix
Recently, a woman with fulminant hepatic failure received a heterotopic, auxiliary,
pig liver xenograft as a temporary "bridge" in an attempt to stabilize her condition
until an allograft became available.x
The liver showed signs of function but her
neurologic status did not improve and she died 34 hours after xenografting.
What Kinds of Diseases Could Be Treated By Xenotransplantation?
Any disease that is treated by human-to-human transplants could potentially be
treated by xenotransplantation. The most likely candidates for xenotransplantation in
the near future are people with serious kidney, liver or heart disease, diabetes or
Parkinsons disease. People who need bone marrow transplants may also be
candidates for this kind of transplant.
What diseases might be treated by cellular xenotransplants?
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Cellular xenotransplants may be a way to treat people who have diabetes, Parkinsons
disease or certain other diseases. The treatment would involve replacing specific cells
or tissues which do not work properly because of the disease. For diabetics, these are
the islet cells of the pancreas, and for someone with Parkinsons disease they would
be certain brain cells. In both cases, the cells needed for the transplant are difficult to
obtain from human donors.
What diseases might be treated by extra-corporeal xenotransplants?
People with liver failure might be treated with an extra-corporeal (outside-the-body)
xenotransplant using a healthy pig liver. The patients blood circulation would be
connected for a short while to a pig liver that is kept outside the patients body. In
some cases, this might be all that is needed to allow the persons own liver to recover
and start working again. In other cases, the persons own liver might not recover, but
the transplant team would have more time to try to find a suitable human liver. This
kind of short term procedure is sometimes called a bridge to transplant. In either case
the extra-corporeal pig liver would only be temporary.
Other extra-corporeal xenotransplant treatments may be carried out using only a small
number of living animal cells. For example, the animal cells may be included in a
specialized device, such as a filter system. When the blood of a patient with liver
failure is pumped through this filter system, the animal liver cells are able to do the
work of the patients own liver, at least for a short while.
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Why do we need xenotransplantation?
The development of xenotransplantation is, in part, driven by the fact that the demand
for human organs for clinical transplantation far exceeds the supply. It is generally
accepted that there is a shortage of human organs for the purpose of transplantation.
Currently only 5 % of the total organs required for transplantation is available. At
present approximately 6000 and 45000 patients await transplantation in the UK &
USA respectively, almost 3000 Canadians are awaiting an organ transplant.ix
and the
number is steadily increasing by 10-15 % each year. Currently ten patients die each
day in the United States while on the waiting list to receive life-saving vital organ
transplants. Moreover, recent evidence has suggested that transplantation of cells and
tissues may be therapeutic for certain diseases such as neurodegenerative disorders
and diabetes, where, again human materials are not usually available.i
Xenotransplantation offers the potential for an unlimited supply of healthy donor
organs. As waiting lists lengthen, many patients decompensate while waiting for a
transplant. Xenotransplantation could be performed electively and timed so that both
the donor and recipient are in optimal condition before transplantation.
Moreover, the donor animal could be matched or manipulated, or both, to facilitate
long-term acceptance of the graft without the need for maintenance
immunosuppression. Before xenotransplantation can be offered to patients, a number
of hurdles must be overcome, including immunologic barriers, disease transmission,
physiological differences and ethical concerns.xi
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What are the risks/hurdles faced in xenotransplantation?
The immunologic reaction
The immunologic reaction of the recipient to a xenograft is mediated initially by
xenoreactive antibodies, complement and natural killer cells and later primarily by
cellular immune responses. These mechanisms result in hyperacute, acute vascular,
cellular and chronic graft rejection.
Hyperacute rejection is a major barrier to discordant xenotransplantation. Humans
have natural IgM antibodies (xenoreactive antibodies) to 1,3-galactose, a
carbohydrate that is expressed on all nucleated pig cells. After binding of these
preformed antibodies, serum complement is activated, resulting in massive
thrombosis to vascular endothelium with vessel occlusion and graft failure within
minutes to hours of the transplantation.xii
Xenoreactive antibodies can be removed by
adsorption columns, but this is only a temporary solution. A more promising approach
is to create transgenic pigs expressing selected human genes that modify the immune
response. Recently, pigs have been raised that express human complement regulatory
genes, thereby preventing activation of complement and ameliorating hyperacute
rejection.xiii
The next major hurdle is to prevent acute vascular rejection which leads to graft
destruction over a period of days to weeks. Xenoreactive antibodies, macrophages,
natural killer cells and complement appear to play important roles in this process.1
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Later (in days to weeks), xenografts may also be damaged by cellular and chronic
graft rejection. It is not known whether any of these processes can be reliably
prevented by currently available immunosuppressive drugs.
viii
It has been evaluated different combinations of antirejection drugs for
xenotransplantation in a baboon-to-monkey model and the results have been
promising. The combination of cyclosporine, cyclophosphamide and rapamycin
provided long-term survival in concordant kidney xenografts. One monkey with a
baboon liver lived for 3 years, despite withdrawal of all immunosuppression 1 year
after transplantation.viii
Ultimately, the goal of transplantation is to attain a state of tolerance whereby the
recipient's immune system accepts the graft as "self" without the need for
maintenance immunosuppression.viii
The opportunity to genetically manipulate pig
donors provides new ways to induce tolerance to xenografts in humans. Donor bone-
marrow transplantation, radiation and the production of monoclonal antibodies
directed against specific lymphocyte receptors are currently being studied as methods
to induce tolerance.viii
What is immune rejection?
Our immune system protects us from things that are foreign, or not normally part of
our healthy bodies. The most common threats to our health are germs, such as viruses
or bacteria all around us. When foreign materials of any kind gets into our bodies, our
immune system kicks into high gear by developing antibodies and specialized white
blood cells to get rid of them.
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What happens when immune rejection occurs during human-to-human organ
transplants?
Except for identical twins, each persons cells are slightly different from everyone
elses. This is the reason that testing is done to find the right match between an organ
donor and the person who needs the transplant. But a perfect match is rarely possible.
Most times, the transplant patient gets an organ that is only as close as possible under
the circumstances. As a result, the patients immune system recognizes the cells of the
new organ as slightly different than its own and tries to destroy these cells, just as if
they were foreign bacteria or viruses. If the patients immune system is successful,
then so much of the new organ is damaged or destroyed that it cant work properly
and we say its been rejected by the patient.
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Can immune rejection be overcome in human-to-human organ transplants?
The development of new immunosuppressive drugs is one of the reasons that human-
to-human transplants are now so successful. These drugs suppress the patients
immune system, not allowing it to work as well as usual and giving the patients body
a much greater chance of not rejecting the transplanted organ. Patients who receive
human organs must usually take immunosuppressive drugs for the rest of their lives.
How does immune rejection work with whole organ xenotransplants?
When whole animal organs are used as xenotransplants, the problems with immune
rejection are huge because animal and human tissues are so different. In fact, the
organs may be so mis-matched that the xenotransplanted organ may be rejected
within minutes of the transplant.
Is it possible to overcome immune rejection with whole organ xenotransplants?
Until recently it seemed impossible to overcome this. Even immunosuppressive drugs
werent powerful enough to stop rejection in the few patients who had received whole
animal organs. However, recent scientific advances may help solve some of these
rejection problems. One solution may be the development of transgenic animals,
where the animals are bred with specific human genes. The principle behind
developing transgenic animals is this: the human gene present in the animal cells will
help to reduce the chances of immune rejection in the xenotransplant patient. Pre-
clinical studies suggest that this approach might work, at least for short term
xenotransplants.
What about immune rejection of xenotransplants over the long term?
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Although xenotransplants from transgenic animals may reduce the possibility of short
term immune rejection, the longer the xenotransplant remains in the patient, the
greater the chance the immune system will recognize it as foreign and start to reject it.
At this time, even with the combination of transgenic animals and immunosuppressive
drugs, the problems of immune rejection are not entirely solved.
Is immune rejection also a problem for extra-corporeal and cellular
xenotransplants?
Extra-corporeal whole organ xenotransplants may also be affected by immune
rejection and often stop working after a very short time because of widespread tissue
damage. However, some cellular xenotransplants seem better able to resist immune
rejection. For example, cells implanted within the brain are somewhat protected from
immune rejection. Xenotransplants of pancreatic islet cells into diabetic patients may
be encased in a special membrane that helps protect them from immune rejection.
Physiologic incompatibilities
There may be physiologic incompatibilities with some xenografts. For example,
patients with porcine kidney grafts may require supplemental erythropoietin to
maintain normal hemoglobin levels. It is unlikely that pig livers will be able to
provide all of the functions of the more than 2600 proteins and enzyme systems that
are produced in human livers. Finally, the lifespan of pigs is less than 15 years;
whether their organs will work for a human lifetime is unknown. There is limited
information about the function of xenografts in humans. Previous attempts at clinical
xenotransplantation, however, have shown that adequate function may occur early
after transplantation.viii
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ERVs
A group of viruses called endogenous retroviruses (ERVs) are of particular concern.
Instead of actively causing infections like other retroviruses, the endogenous
retroviruses remain dormant in their host - embedded in the genetic material - not
causing any obvious signs of disease. However, they may be activated occasionally,
and it is possible they could then infect other animals, including different species.
Little is known about what might make endogenous retroviruses become active but, if
an animal transplantation product contains an endogenous retrovirus, there is the
potential for it to activate at any time in the future and infect the transplant recipient
.Such an infection could spread to close contacts of the recipient (for example,
medical staff, family, friends) and, in the worst case, to the general population. These
ERVs cannot be screened out.viii
These are known to cause Xenozoonosis, which is
defined as the infection of a pathogen from an animal to a human being due to the
introduction of xenograft.vii
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PERVs
Most pigs have a retrovirus called porcine endogenous retrovirus (or PERV). In
1997 researchers reported that when they mixed pig cells with human cells in the
laboratory, some human cells became infected with PERV. The first evidence of
cross-species transmission of a retrovirus during a transplant occurred in 2000, when
a study found transmission of a PERV from pancreatic pig cells into
immunosuppressed diabetic mice. This raises the possibility that the recipient of a
pig transplant may be infected with PERV, or with another, currently unknown,
infectious disease agent. Some retroviruses have been associated with cancer.ix
It seems likely that the risk of unusual infections will be low since humans and pigs
have lived in close proximity for many years. Moreover, many immunocompromised
patients have been treated with full-thickness pig skin grafts with no evidence of
adverse effects. Nonetheless, xenotransplant recipients, their families and their health
care providers will have to be monitored closely for infectious complications.viii
Public health risks
If the xenotransplant procedure involves a risk not only to the recipient but also to
close contacts - and in the worst-case scenario of an epidemic, a risk to everybody -
individual consent becomes insufficient.
The ethical question then becomes:
is it right to impose risks on people without their consent?
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options include only chronic dialysis or ventricular assist devices. Popma and
colleagues[2]
demonstrated that the presence of allosensitization in 7 individuals was
accompanied by concomitant "cellular xenosensitization" -- ie, higher T-cell
proliferative responses to porcine endothelial cells when compared with T-cell
proliferative responses of nonsensitized individuals. We have previously reported
that nonsensitized human subjects have an increased proliferative response to pig
endothelial antigens in comparison to alloantigens, and that this is related to direct
xenorecognition of pig SLA by CD4 T cells. This suggests that the same
mechanisms that lead to CD4 T-cell sensitization against alloantigens may also
predispose the individual to a state of heightened immune activation directed against
pig xenoantigens. Since the allosensitized state is associated with an increased
incidence of humoral and cellular rejection of allografts, these data suggest that the
highly sensitized allorecipient may not be the most appropriate initial choice for
transgenic pig xenografts using currently available immunosuppressive regimens.
Modification of Immunosuppressive Regimens in an Attempt to Improve Pig to
Nonhuman Primate Xenograft Survival
For the past several years a select group of institutions working in conjunction with
the manufacturers of transgenic pig xenografts have attempted to achieve
prolongation of graft survival beyond days. Unfortunately, this has not yet
consistently been achieved using the currently available transgenic constructs. At
first it was thought that a more aggressive immunosuppressive regimen might lead
to prolonged graft survival. As yet, this has not been achieved and the median
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orthotopic working heart graft survival remains 12 days, with the longest survival
slightly less than 1 month. Interestingly, a small group of animals continue to
hyperacutely reject the transgenic xenograft. Brenner and colleagues
report their
experience with hDAF transgenic heterotopic and orthotopic heart xenografts using
a fairly intensive drug therapy, which in some animals also included
immunoadsorption. Not unlike the previously described morbidity seen by the Loma
Linda group with xenotransplantation between closely related species, these animals
experienced significant morbidity related to the drug therapy without a survival
advantage. In particular, despite this aggressive immunosuppression, these animals
continued to succumb to acute vascular rejection, a second barrier that had to be
overcome for successful pig-to-primate xenotransplantation. These experiments
emphasize the need to better understand the mechanisms involved in acute vascular
rejection, as well as the need to develop additional transgenic constructs that may
better resist these immunologic barriers, such as multiple complement regulators and
approaches that enable reduced expression of pig xenoantigens.
Xenotranplantation : Cultural, spiritual and Ethical Issues
Not all members of the medical profession may be comfortable with
xenotransplantation. Several questions come immediately to mind: Do we really need
xenotransplantation? Does xenotransplantation alter our definition of a human being?
Are we transgressing the laws of nature? Does life need to be prolonged at any price?
What are the psychological and biological effects of xenotransplantation on the
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recipients? What are the implications for society, and for future generations? What are
the effects on animals? Do we care about animal suffering and genetic manipulation
of animals?
iv
Religious viewpoints
As an indication of religious viewpoints, the Australian public consultation on
xenotransplantation received submissions from representatives of the Christian,
Jewish and Islamic religions, who agreed that xenotransplantation does not
contravene the order of creation, and that the use of animals for human benefit is
acceptable. A review of world religions found that xenotransplantation is acceptable
in most of the major religions. Both Islam and Judaism forbid the eating of pork, but
accept xenotransplantation on the basis that humans have a higher place in the world
and therefore have the right to use animals for their welfare, as long as the animals are
treated with respect. A number of religions that do object to transplantation, such as
the Hindu or Buddhist faiths, still allow the individual to make a choice.viii
Identity
Some organs (especially) and tissues are more related to an individual's sense of
personal identity than others. Would - or in fact should - the particular tissue, cells or
organ involved alter our thinking about xenotransplantation?
Consider the transfer of a number of pig pancreas cells to a person suffering from
diabetes. Compare this to a person who has been given a pig's heart, or perhaps even a
pig's eyes.
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Is there a point at which the person receiving the transplant, or other people, would
feel that he or she was now less human? That somehow their personal identity had
been compromised?
viii
The Interests of Animals
Animals likely to be used in xenotransplantation
Non-human primates
Researchers, research sponsors and the wider community generally agree that non-
human primates (such as baboons and other monkeys) are not a suitable source for
any of the proposed animal therapies (external therapies, cell therapies or organ
transplants) because of the risk of infections to the recipient and the wider
community. The US Food and Drug Administration has effectively prohibited the use
of non-human primates in animal-to-human xenotransplantation since 1999.
The use of non-human primates in medical research also raises serious ethical issues.
Non-human primates are highly intelligent animals with complex behavioural and
social needs that are difficult to meet in a medical research environment. However,
baboons are considered the most suitable species for animal-to-animal studies (such
as pig to baboon) to obtain important information on the effectiveness of a procedure
before it can be tested in an animal-to-human trial.
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Pigs
At present, pigs are considered to be the most likely and appropriate non-human
source of organs and tissues. The anatomy and functioning of pigs are very similar to
those of humans. Pigs are domesticated animals that are easy to breed, and,
importantly, pigs are suitable for genetic modification.
Other animals
Animal-to-animal transplantation studies would use a variety of animal species in the
early stages of the research (such as mice, rats and rabbits). If these studies show
promising results, researchers will need to trial the procedure in an animal study that
is as much like the future clinical use of the therapy as possible. This will usually
involve the use of non-human primates (specifically baboons) as transplant recipients,
as noted above, but fish and cattle might also be used for some procedures, such as
helping to grow skin. Researchers are also considering the use of other species (such
as cattle, fish and mice) for cellular transplants.
Which animals work best?
It would seem obvious, when searching for ways to reduce the rejection reaction to
xenografts, to use animals as physiologically close to humans as possible, such as old
world monkeys and the apes (for example, chimpanzees). However, this very
closeness creates complex ethical problems as well as an increased likelihood of
cross-species infection. There are strict regulations in New Zealand about the use of
non-human primates in research, so it is unlikely that these species would be used for
xenotransplantation research in this country.
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At present the pig is the favoured animal for research into xenotransplantation,
because they grow quickly to about the right size, produce large litters and can be
reared in specific pathogen-free conditions (where some but not all micro-organisms
are excluded). In terms of ethical concerns, the fact that pigs have long been used as a
source of meat reduces - but certainly does not eliminate - the concerns of many
people, especially when weighed against the possible benefits. However, recently it
has become clear that there is also the possibility of cross-species infection from pigs.
This takes the issue of whether to perform such a procedure out of the realm of an
individual decision to take a personal risk, usually for the sake of a therapeutic effect,
into the realm of the safety of the xenotransplantation recipient's close contacts and
the community at large. The spectre of HIV and AIDS hangs over discussions on the
possibility of cross-species infection, so we will now turn to look at the risks involved
with xenotransplantation.
Genetic modification of animals
This raises some difficult ethical issues about the rights and welfare of the animals,
such as whether the insertion of human genes may make the animal in some way
'human', or whether inserted genes cause unexpected side-effects in the animals. One
view may be that these issues need to be considered case by case to ensure that the
proposed modification does not alter the animal in any other significant way. The aim
would be to ensure that the animals retain the essential characteristics of their species.
Animal welfare and ethics
Some think it is wrong to cause suffering to or kill animals even if this has major
benefits. Such an argument might be based on the belief that humans and animals
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have the same moral status. It is a matter of controversy how much suffering
xenotransplantation experiments and rearing would cause. For example, some types of
xenotransplantation involve killing young pigs under anaesthesia, whereas others
involve the destruction of a chimpanzee's immune system through chemotherapy and
radiation. To minimise the risk of cross-species infection, source animals for
xenotransplantation would probably need to be bred and raised in monitored,
biosecure facilities. The adverse effects on animals could give rise to particular
concern, especially since these source animals would need to be raised in isolation.
Is a xenotransplant intended to be permanent?
Not always. While organ transplants are generally intended to be permanent, some
kinds of transplanted cells may need to be replaced regularly in order to function well
and remain vital. Also, certain kinds of xenotransplants are not really true transplants
at all, because the animals organ or cells stay outside the patients body and are used
only in the short term, often as a bridge to transplant
How is scientific research on xenotransplantation carried out?
Research on xenotransplantation follows the same steps as research into any other
treatment for human disease. The first step involves studies that are carried out in the
laboratory and/or on animals. These kinds of studies are called pre-clinical trials.
They do not involve human patients.
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Many xenotransplantation studies have been carried out using laboratory animals. As
well as increasing scientists understanding of how well xenotransplantation works or
does not work, they have helped scientists understand how xenotransplantation might
be made safer and more successful for treating patients.
When pre-clinical studies show that the treatment is safe and effective in animals, the
new treatment or therapeutic product is tested on patients, under very controlled
conditions. This kind of testing is called a clinical trial or a clinical study. Usually,
only small numbers of patients are involved. They volunteer to take part in the
research and consent only after the potential risks and benefits of the study are fully
explained to them. In Canada and in many other countries, clinical studies must be
approved by a regulatory authority, usually a government health department or related
agency.vii
In Canada, Health Canada regulates clinical trials involving xenotransplants. As of
March 2000, no clinical trials have been approved by Health Canada.vii
Xenotourism
Xenotourists are people who, in desperation, travel overseas to countries that do
allow xenotransplantation, undergo the procedure and then return to their country
where xenotransplantation is prohibited. Because this may be done covertly there
would be no possibility of even minimal monitoring of such people.
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As a result, the management of these risks needs to be considered as these
xenotransplantation could be performed perhaps without the careful selection and
husbandry of source animals needed to reduce the risk of cross-species infection.
The kinds of public health measures needed to manage the movement of
xenotourists would be ethically controversial, and could include:
a requirement to disclose information about xenografts to medical authorities
a register of recipients
regular checks on the health of recipients, including taking blood samples
informing the recipient's relations and close contacts that they have had
xenografts
restricting the travel of recipients
(in extreme cases) quarantining recipients.
And, of course, anyone who has previously received an animal transplant will need
to be excluded from donating any of their organs or tissues in the future. This rule
will need to apply in all countries, including those that operate a presumed consent
system for organ donation. These measures might be justifiable if the recipients
accepted these as conditions for undergoing xenotransplantation.
Some believe that, given the difficulties of regulating xenotourism, it would be
better to have well-regulated xenotransplantation here than to take the risk of people
going to less well-regulated countries for xenotransplantation and bringing disease
back.
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Myths of Xenotransplantation
The myths of xenotransplantation as explored by Jeffrey Platt, MD, of the Mayo
Clinic in Rochester, Minnesota.The myths that were explored included
(1) xenotransplantation is a new idea,
(2) xenotransplantation will only happen far into the future,
(3) the major problem in xenotransplantation is infectious disease, and
(4) the safest approach to xenotransplantation is continued bench research without
clinical trials.
Dr. Platt contended that xenotransplantation is not a new idea and it is not only for the
future. Xenotransplantation was first attempted in the early years of the 20th century.
On a limited scale, xenotransplantion is occurring today. Among the xenotransplants
currently used are fetal porcine central nervous system tissue for the treatment of
Parkinson's disease and porcine skin for the treatment of burns. Porcine livers are also
used via ex vivo perfusion to cleanse the blood of human patients with liver failure.
While it is commonly thought that the major problem in xenotransplantation is
infectious disease, it may well be that xenotransplantation will contribute a solution to
the problem of infectious disease. As opposed to an allograft, it may be possible to
define the infectious disease risk of transplantation with a xenograft. More to the
point, it is possible that a xenograft could be used to avert reinfection of a transplanted
organ that would inevitably occur if a human organ were used.
Finally, Dr. Platt argued that the safest approach to xenotransplantation is not
continued research without clinical trials. First, bench research may have its own
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risks. Xenogeneic tissues, even human tissues, are commonly transplanted into
immunodeficient rodents, and it is possible that recombination of viral genes could
lead to emergence of a human pathogen. Yet, this possibility is not monitored, as it
would be in clinical xenotransplantation research. In addition, clinical
xenotransplantation could be viewed as a model system to study the potential
pathogenicity of animal viruses. The assessment of such pathogenicity could allow the
development of measures to prevent entry of pathogenic virus into humans through
domestic or commercial endeavors.
Future Directions: Genetic Engineering
Genetic engineering could be used to generate sources of xenografts able to resist
tissue injury and rejection. Typically, xenoreactive antibodies, complement,
macrophages, and the natural killer cells of a xenograft recipient may react with the
xenograft to trigger activation of endothelial cells. Instead of inhibiting thrombosis
and inflammation, the endothelial cells that are activated promote thrombosis and
inflammation, and undergo apoptosis. Most efforts in the genetic engineering of pigs
as a source for xenografts have focused on abrogating the initiation of xenotransplant
rejection, thus decreasing the expression of antigen and bringing about the expression
of complement regulatory proteins. However, Dr. Soares asserted that the use of
genetic engineering to modulate endothelial cell activation could potentially be of
value.
A common event in the activation of endothelial cells is the induction of apoptosis.
Accordingly, efforts might be made to inhibit apoptosis. Several genes believed to
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function in this regard, ie, A20 and heme oxygenase-1 (HO-1), have been explored.
The potential contributions of HO-1 were discussed.
HO-1 degrades heme, a prosthetic group of proteins such as hemoglobin, to yield
carbon monoxide and iron. The organs from knockout mice lacking HO-1 are rapidly
rejected by xenogeneic recipients. Similarly, treatment of recipients with tin
protoporphyrin, which inhibits HO-1, leads to rapid rejection of xenografts. These
results suggested that HO-1 is protective against xenograft injury, especially
reperfusion injury because the active product of HO-1 may be carbon monoxide.
Treatment of xenograft recipients with carbon monoxide inhibits platelet aggregation
and monocyte activation, and appears to prolong the survival of xenografts.
US FDA Guidelines
Purpose
To provide a comprehensive approach for the regulation of xenotransplantation that
addresses the potential public health safety issues associated with xenotransplantation
and to provide guidance to sponsors, manufacturers and investigators regarding
xenotransplantation product safety and clinical trial design and monitoring.
Regulatory Policy and Guidance Development
Xenotransplantation products are subject to regulation by the FDA (e.g., under section
351 of the Public Health Service Act (42 U.S.C. 262) and the Federal Food, Drug and
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Cosmetic Act (21 U.S.C. 321 et. seq.)). In accordance with the statutory provisions
governing premarket development, xenotransplantation products are subject to FDA
review and approval. Investigators of such products should obtain FDA review of
proposed xenotransplantation clinical trials before proceeding.
FDA intends to publish guidance documents to assist sponsors and investigators
interested in conducting clinical trials in the field of xenotransplantation. These
documents will provide reasonably detailed and timely pragmatic guidance to
sponsors regarding xenotransplantation product safety and clinical trial development,
including specific recommendations for the procurement and screening qualification
of source animals, the manufacture and testing of xenotransplantation products,
preclinical testing, clinical trial design, and post-transplant monitoring/surveillance of
recipients of xenotransplantation products. FDA will provide notice and invite public
comment on these draft documents.
Application Review
Currently, several xenotransplantation clinical trials are under FDA oversight. In
order to respond efficiently to the data submitted to the agency in xenotransplantation
product applications, CBER has developed a mechanism for the systematic and
regular evaluation of the scientific and clinical literature relevant to
xenotransplantation and submissions to xenotransplantation product files. A
Xenotransplantation Product Reviewer Working Group, consisting of the review staff
responsible for the review of xenotransplantation submissions (clinical, product, and
pharm-tox reviewers, and veterinary staff) meets regularly to:
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discuss application of the principles set forth in relevant FDA regulations,
review and discuss current scientific and medical data and literature relevant
to xenotransplantation
review and discuss the current status of xenotransplantation applications
submitted to the agency
discuss the unique issues that these products may present
highlight areas of concern where further expert advice may be needed
This provides for a consistent review of xenotransplantation applications and should
facilitate the recognition of patterns, trends, and/or common problems that may be
associated with xenotransplantation products. This data evaluation and management
process is linked to the regulatory process and is applied during regulatory decision
making and policy design.
Scientific Investigations and Research
Research conducted at CBER has been instrumental to the understanding of safety
issues associated with xenotransplantation. CBER is engaged in scientific
investigations of known and emerging infectious agents and immunological hurdles
that will need to be overcome for the safe and effective use of xenotransplantation
products. The results of these studies have helped CBER in its safety assessment
including assessment of risk and the development of diagnostic methods and
standards. CBER researchers continue to develop assays appropriate for safety
monitoring and are working with sponsors and collaborating with other government
scientists in this development.
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These research scientists apply their unique expertise in performing regulatory review
and to the development of regulatory policy for xenotransplantation. Working groups
analyze data and events, develop and propose strategies for appropriate studies, risk
assessment, prevention, communication and agency response or regulatory action
(e.g., request for more data from sponsors, request for particular product assays,
placement of clinical hold) and discuss these proposals and strategies with advisory
committees when needed or at public meetings as appropriate.
This process provides improved coordination of efforts to address the potential safety
issues associated with xenotransplantation and provides a mechanism whereby
infectious agents and diseases that may be associated with xenotransplantation can be
rapidly recognized and an appropriate and timely regulatory response generated.
Public Discussion and Consultation
FDA has sponsored, planned or participated in numerous open public meetings and
orkshops, both domestic and international that focused in whole or in part on
xenotransplantation. These activities are essential for both sharing information and
receiving public input on issues relevant to xenotransplantation.i
In 1997, FDA formed a Xenotransplantation Subcommittee of the Biological
Response Modifiers Advisory Committee (BRMAC) as an ongoing mechanism for
open discussions of the scientific, medical, social, and ethical issues and the public
health concerns raised by xenotransplantation, as well as specific ongoing and
proposed protocols. Open public meetings update the committee and the general
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public on the issues associated with xenotransplantation and the development of FDA
policy regarding the regulation of xenotransplantation products.i
DHHS Xenotransplantation Committee
The DHHS Xenotransplantation Committee oversees departmental initiatives to
address the public health issues raised by xenotransplantation. It is comprised of
members from FDA, CDC, NIH and HRSA and is administered through the Office of
the Assistant Secretary for Planning and Evaluation/Office of Science Policy.i
DHHS has established the Secretary's Advisory Committee on Xenotransplantation
(SACX), which will consider the full range of complex scientific, medical, social,
ethical, and public health concerns raised by xenotransplantation, and make
recommendations to the Secretary on policy and procedures.i
Guidance for Industry
Source Animal, Product, Preclinical, and Clinical Issues Concerning the Use of
Xenotransplantation Products in Humansi
I. REGULATORY RESPONSIBILITYII. SOURCE ANIMAL CHARACTERIZATION
A. General ConsiderationsB. Animal Welfare ConcernsC. Animal Origin
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D. Animal Health and HusbandryE. Harvest of Nonhuman Live Cells, Tissues or Organs for Use in
Producing Xenotransplantation Products
F. Source Animal History for Xenogeneic Cell LinesG. Disposal of Animals and Use of Byproducts
III. CHARACTERIZATION OF XENOTRANSPLANTATION PRODUCTSA. General ConsiderationsB. Considerations for Classes of Xenotransplantation Products
IV. MICROBIOLOGICAL TESTING OF XENOTRANSPLANTATIONPRODUCTS
A. General ConsiderationsB. Considerations for Classes of Xenotransplantation ProductsC. Assay Design for the Detection of Infectious Agents
V. MANUFACTURING AND PROCESS-RELATED GMPCONSIDERATIONS FOR HARVEST AND PROCESSING OF
XENOTRANSPLANTATION PRODUCTS
A. General ConsiderationsB. Contamination/Cross-Contamination PrecautionsC. Validation and Qualification
VI. PRECLINICAL CONSIDERATIONS FOR XENOTRANSPLANTATIONA. General ConsiderationsB. Issues Related to Infectious AgentsC. Xenotransplantation Product-Host InteractionsD. Considerations for the Use of Heterogeneous Xenotransplantation
Products
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E. In Vitro and In Vivo Tumorigenicity Models for Xenotransplantation
Products Intended for Transplantation
F.
Combinations of Xenotransplantation Products with Devices
VII. CLINICAL ISSUES IN XENOTRANSPLANTATIONA. General ConsiderationsB. Clinical Protocol ReviewC. Xenotransplantation SiteD. Criteria for Patient SelectionE. Risk/Benefit AssessmentF. Screening for Infectious AgentsG. Patient Follow-upH. Archiving of Patient Plasma and Tissue SpecimensI. Health Records and Data ManagementJ. Informed Consent
K. Responsibility of the Sponsor in Informing the Patient of NewScientific Information
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Summary
The tremendous need and urgency for donor organs have provided a great stimulus to
creative scientific investigation in the field of xenotransplantation. The success in
overcoming the immediate barrier of hyperacute rejection has driven some
investigators to consider clinical application of transgenic pig-to-human
xenotransplantation. The lessons learned from the series of presentations at this
meeting include a cautionary note regarding the use of allosensitized humans as
appropriate recipients of pig xenografts; the need for further understanding of the
immune mechanisms involved in acute vascular rejection, cellular rejection, and
chronic rejection; and the complexities in immunomodulation of the xenograft. Every
animal model has its limitation, and the need to proceed to the clinical arena with
novel therapies must take into consideration the limitations imposed by the particular
animal model tested. Some questions will eventually only be answered by
appropriately selected clinical application.
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G l o s s a r y o f W o r d s a n d P h r a s e s
Allosensitization - Exposure to an alloantigen that induces immunologic memory
cells.
Bridge to transplant - a short term procedure using an extra-corporeal
xenotransplant that could buy a patient time until a human organ becomes available.
Clinical trials, clinical studies - research studies on new drugs or treatments which
are carried out with human patients. The patients volunteer for this research and
consent only after the potential risks and benefits of the study are fully explained to
them.
Endogenous retrovirus - many species of mammals, including humans, have certain
kinds of viruses or fragments of viruses in their cells. These are embedded in their
DNA and are passed from one generation to the next, usually without causing any
harm in the host species, for example PERVs.
Extra-corporeal - outside the body; sometimes called ex vivo. The term refers to
certain kinds of xenotransplants which are not true transplants at all, because the
animal organ or cells are connected to but stay outside the patients body.
Immunosuppressive drugs - drugs which reduce the effectiveness of a patients
normal immune system. They are given to patients who have received (human)
transplants so that their immune system wont reject the new, slightly mis-matched
organ.
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Immune rejection - a patients immune system will normally accept a transplanted
organ (from either a human or an animal donor) only if its a fairly close match with
its own tissue type. Antibodies and special white blood cells will attack the foreign
cells in the transplant, and damage it so much that it cannot work properly. When this
happens, doctors say that the patients immune system has rejected the new organ. It
usually has to be removed.
Medical device - a combination of biological materials such as animal cells, and other
materials such as an artificial membrane or filter system.
Microorganisms - very small living organisms such as viruses, bacteria or fungi that
may cause infection and disease. Commonly known as germs or infectious agents.
Non-human primates - the group of animals which is biologically most similar to
humans, including chimpanzees, baboons and monkeys.
PERVs- stands for pig (or porcine) endogenous retroviruses. PERVs have been a part
of all pig cells for thousands of years. They are not active and are normally harmless
to the pigs.
Pre-clinical studies - research studies on new drugs or treatments which do NOT use
human patients. Pre-clinical studies are confined to laboratory or animal studies.
Risk to third parties - refers to the indirect risk that people other than the
xenotransplant patient might be exposed to. (The pig and the xenotransplant patient
are considered to be the first two parties in the risk equation.) The risk to third parties
refers to the possibility that a xenotransplant patient might be infected with an
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infectious agent, such as a virus, from the xenotransplant, and that this infection might
be passed on to other people through intimate or daily contact.
Species specific microorganisms that can only infect one species of animalfor
example pigs or humans.
Transgenic animals - animals that contain a gene (or genes) from another kind of
living organism, for example, pigs which contain a human gene.
Xeno - is used as a prefix and means strange or foreign.
Xenotransplant or xenograft - the living animal material that is transplanted into
humans in xenotransplantation.
Xenotransplantation - a transplant procedure in which a human patient receives an
organ (such as a kidney or liver) or living cells (such as brain cells) that come from a
healthy animal instead of from a human donor. The same term can be used to describe
a transplant between any two different species of animals.
Xenozoonosis (plural xenozoonoses) - zoonotic diseases that might be passed from
animals to people by means of a xenotransplant.
Zoonoses, zoonotic infections - microorganisms carried by animals, which can also
infect and/or cause diseases in humans under normal (non-transplant) conditions.
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1
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