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TECHNOLOGIES
Xenotransplantation
While work to combat immune rejection of animal organs is progressing,
concerns remain as to the risks of disease transmission.
There are more than five times as many peo- transplantation diminished, in part because marrow from the donor to reeducate the
ple on the waiting list for organ transplants as rejection based on preformed antibodies recipient’s immune system to accept the
will actually receive one. Although the num- became an insurmountable problem. In donor organ as self.
ber of transplants increased by about 30% addition, the development of hemodialysis, Under the agreement, Novartis obtained
during the 1990s, the number of candidates coupled with greater human organ availabili- a worldwide license to the technology in
doubled. This acute shortage of human ty as a result of the public’s acceptance of the exchange for license payments, research
organs has prompted significant research and notion of brain death, created a false sense of funding, and milestone payments to
development into alternatives, specifically security about the real need for organ trans- BioTransplant totaling $36 million. In addi-
xenotransplantation, defined as the trans- plants. However, the increase in transplant tion, BioTransplant will receive royalties on
plantation of organs from other animal candidates in this decade, and the ensuing eventual sales, and retains the right to copro-
species into humans. quantitative crunch from an outstripped mote products resulting from the collabora-
This approach is under investigation for a supply, has ultimately led to a resurgence of tion in North America under certain circum-
wide range of conditions, including replace- interest in xenotransplants as a source of stances. This agreement extends an existing
© 2000 Nature America Inc. • http://biotech.nature.com
ment of the heart, lungs, liver, and kidneys. organs, especially for children. agreement between the two companies cov-
Xenotransplantation is also being developed ering a gene therapy approach to create toler-
for non–whole organ scenarios such as dia- Current state ance in xenotransplantation.
betes, neurodegenerative disorders, chronic Current interest in xenotransplantation is Novartis entered into an additional
pain control, and ex vivo perfusion events. fueled by promising results and significant xenotransplantation agreement in 1997,
Research has focused in large part on pig demand. In addition to academic clinical this time with T-Cell Sciences (now Avant).
organs and tissues because their biochemi- work, there is considerable corporate interest This is a $25 million option and license
cal profile is similar to that of human in the field. Table 1 shows a selection of agreement for the development of TP10, T-
organs. However, associated with all types of biotechnology and pharmaceutical compa- Cell Sciences’ lead complement inhibitor5,
xenotransplantation are some significant nies with xenotransplantation programs. for use in xenotransplantation and allo-
problems, including hyperacute rejection, There are also several strategic alliances transplantation (human to human). Avant
delayed rejection, and cell-based immune in this area. In 1997, BioTransplant and will receive annual option fees and supplies
rejection. Additionally, novel infections may Novartis Pharma expanded their two-year- of TP10 for clinical trials—the combination
be transmitted from the donor to the recipi- old xenotransplantation collaboration to of which is valued at up to approximately
ent and spread to the human population. include BioTransplant’s technology, which $5 million—in return for granting Novartis
There is considerable debate over the pros creates transplant tolerance by a mixed a two-year option to license TP10 with
and cons of xenotransplantation, and the bone marrow chimerism approach. The exclusive worldwide marketing rights
US and the UK have already taken signifi- technology involves transplanting bone (except for Japan), in the fields of xeno-
cant regulatory steps to foster this debate
and to control clinical trials. Several compa-
Table 1. Selected companies with xenotransplantation programs
nies are pursuing xenotransplantation in
step with the regulatory frameworks, as the Company Program
potential market for this procedure is
believed to be significant. Alexion Pharmaceuticals Xenograft tissues
(New Haven, CT)
Avant (Needham, MA) Complement inhibition in xenotransplantation
Historical perspective
BioTransplant (Charlestown, MA) Mixed bone marrow chimerism
The first attempts to use animal organs in Chromos Molecular Systems Mammalian artificial chromosomes
humans were reported in the early 1960s, (Vancouver, BC, Canada) for xenotransplantation
involving the transplantation of chimpanzee CytoTherapeutics (Providence, RI; Chronic pain relief by encapsulated xenotissues
kidneys. The results were significant: one acquired by Stem Cells Inc.)
patient survived for nine months with nor- Diacrin (Charlestown, MA) Xenotransplantation for intractable epilepsy,
Huntington’s disease, Parkinson’s disease
mal kidney function before dying from the
Genzyme (Cambridge, MA) Xenotransplantation for Huntington’s disease,
effects of immunosuppression, while another Parkinson’s disease
had a rejection episode that was relieved by Imutran Ltd Porcine kidney xenografts,
steroid therapy1,2. These results showed that (Cambridge, UK) pig liver xenotransplantation
xenograft survival and function was possible InCell (Fremont, CA) Electrical pulse delivery (EPD) gene transfer method
and could last for considerable periods of Nextran (Princeton, NJ) Anti-CD45 monoclonal antibodies for the prevention
of organ rejection; anti-CD3 humanized
time, despite the relatively poor immunosup-
monoclonal antibody for the treatment
pression protocols then available. of acute organ rejection
Following these efforts, baboon-to- Novartis Pharma (Basel, Switzerland) Protective monoclonal antibodies
human heart, liver, and kidney transplants SangStat Medical Corp. (Menlo Park, CA) Immunoglobulin infusion in xenotransplantation
were attempted, none of which achieved one- United States Surgical Corp. (Norwalk, CT) Xenograft tissues
year survival of either the graft or the Source: Biovista (www.biovista.com)
patient3,4. From then on, interest in xeno-
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TECHNOLOGIES
transplantation and allotransplantation. Cell-based rejection is particularly strong ing basic functional “take,” these patients
Should Novartis exercise its option to in xenotransplants, mimicking that in trans- had no significant reduction in insulin
license TP10 and continue development, it plantation in general; it involves helper and requirement11. Other studies have used fetal
will provide an equity investment, licensing killer T cells and others. There is a consensus pig neural cells in patients with
fees, and milestone payments based upon that the best way to overcome it is not by gen- Huntington’s or Parkinson’s disease.
attainment of certain development and reg- eral immunosuppression, which is insuffi- Although the pig tissue has survived, early
ulatory goals. cient, but by inducing tolerance to specific benefits (i.e., improvements in quality of
xenoantigens before transplantation, for life) for these patients are still unclear12.
Industry challenges example, by the mixed chimerism bone mar- Despite these results, another study reports
Xenotransplantation can be thought of as an row approach described earlier. on the effect of microencapsulated bovine
extreme but necessary solution to a very dif- Even if all of the immunological barriers chromaffin cells on monkey models of
ficult problem, namely irreversible and ter- just described were to be overcome, the final Parkinson’s disease13. The cells were encap-
minal tissue and organ failure. It must deal challenge to the development of xenotrans- sulated in alginate-polylysine-alginate
with two considerable plantation as a viable membranes and resulted in a reduction of
technical problems, The final challenge to therapy is the certain Parkinsonian symptoms for up to
one of which also has prospect of novel nine months compared with controls, sug-
significant societal the development of infections, particu- gesting that this approach merits continued
implications. The first larly viral ones, being clinical interest. Finally, an AIDS patient
has to do with rejec-
xenotransplantation as introduced through has received baboon bone marrow cells to
tion of the organ and a viable therapy is the the recipient into the boost T cell levels but no evidence of graft
cells, and the other is human population. survival was obtained14.
© 2000 Nature America Inc. • http://biotech.nature.com
the risk of introduc-
prospect of novel The debate about the In addition, a major issue for the clinical
ing novel infections infections, particularly viral societal risk posed practice of xenotransplantation is survival
into the human popu- remains unresolved. and longevity of the xenografts. Although
lation.
ones, being introduced However, there is a there is increasing interest in the use of pig
There are essen- through the recipient into renewed effort to organs for this purpose, there is a lack of
tially three types of develop methods of information regarding their longevity and
xenograft rejection, the human population. evaluating the risk, to that of their primate hosts beyond the first
which vary even fur- establish surveillance, month after transplantation. A recent report
ther depending on whether the transplant is to improve virus screening and diagnostic describes how pig kidneys transplanted into
of a whole organ or just cells: hyperacute capabilities, as well as to introduce rigorous immunosupressed monkeys that had their
rejection, with almost immediate onset, clinical trial guidelines, to encourage com- kidneys removed had normal renal function
mediated by preformed and new antibodies munication among all involved, and to estab- and enabled the animals to live for more than
against foreign antigens; delayed lish a permanent oversight body to regulate two months15. Results such as these are
xenograft/acute vascular rejection, with a the procedure, similar to the Recombinant important for the future clinical application
longer time profile and a mechanism that is Advisory Committee of the National of porcine organs as xenografts.
not fully understood, but which is likely to Institutes of Health, which regulates genetic
involve host antibody and immune cell bind- engineering. As an example of this debate, The future
ing to the vascular endothelium of the some are of the opinion that xenotransplan- Although the debate over the risk posed by
xenograft, leading to its destruction; and tation poses a lesser risk of transmitting the infection potential of xenotransplanta-
finally, cellular immune response through known infections to humans than does allo- tion is ongoing, the factors driving its
pathways that are similar to the rejection transplantation8, whereas others focus on the development approaches are more pressing
pathways of allografts and are mediated by unknown risks posed by the multiple animal than ever. The need for human organs is
histocompatibility determinants and other retroviruses, lentiviruses, herpesviruses, and simply increasing faster than their availabil-
cell surface components. other harmful agents that may be found in ity. Validation for the approach will come
There is marked progress in resolving animal donor organs and cells9. with continued improvements in the battle
hyperacute rejection against transplanted against rejection of xenografts. An interest-
cells, mediated by antibodies against the Clinical relevance ing approach is that of using retroviral gene
αGal carbohydrate epitope displayed on the Despite the technical challenges and debate therapy to inhibit the production of
surface of pig cells, for example. Although over xenotransplantation’s acceptability, xenoreactive antibodies, which are involved
preformed and new antibodies are created efforts continue in the clinic to address these in the hyperacute and delayed types of
against this antigen, research suggests that issues. Increasing attention is directed to ex rejection. One study that holds significant
this humoral response can be overwhelmed vivo perfusion through animal livers10. The promise reported the absence of such anti-
simply by transplanting larger numbers of promising results with this significant appli- bodies in an animal model when bone mar-
donor cells6. cation suggest that this avenue will continue row was genetically modified to produce
Delayed rejection is targeted against the to be explored. the enzyme that actually makes the αGal
vascular endothelium of the transplanted Efforts have also been directed at epitope. Production of this epitope thus
organ. Although its mechanism is not well xenografting cells as opposed to whole rendered the animal tolerant16.
understood, it is believed that induced anti- organs in certain conditions. For instance, In the future, cells, instead of whole
body responses are critical. Therefore, atten- clinicians have been attempting to implant organs, will be used for a variety of major
uation of the B-cell response, which is cen- fetal pig islet cells into human diabetic organ diseases. A recent report describes
tral to new antibody production, is being patients. Although one effort by Swedish the xenotransplantation of immortalized
evaluated as a way to overcome this researchers resulted in the survival of the human hepatocytes in rats suffering from
immunological barrier, with promising porcine cells in at least one patient and the experimental acute liver failure17, and these
results in animal models7. production of pig C-peptide, demonstrat- approaches will continue to be explored in
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TECHNOLOGIES
the future. Complementing these Conclusions increasing to address the challenges posed by
approaches will be continued advances in Xenotransplantation, a field with a 30-year the various forms of rejection of xenotrans-
encapsulation technology itself, including history, has received renewed attention plants, and the early results are deepening
agarose/polystyrene sulfonic acid con- recently as a result of promising clinical our understanding of the underlying mecha-
structs18 and others, which will broaden the efforts. It addresses an acute shortage of nisms, as well as helping to define the exact
range of cells that can be used for these nature of the risks involved. Society’s need, in
purposes. Society’s need, in conjunction with clinical efforts and corpo-
On another front, researchers are trying rate interest in this area, promise to keep
to modify genetically the pig organ donors conjunction with clinical xenotransplantation in the limelight as a
themselves, so that they do not present the efforts and corporate technology to watch.
critical epitopes identified and linked with
rejection phenomena. It is believed that a interest in this area, 1. Reemtsma, K. et al. Science 143, 700–702 (1964).
combination of genetic engineering of promise to keep 2. Reemtsma, K. et al. JAMA 187, 691–696 (1964).
3. Hitchcock, C.R. et al. JAMA 198, 934–937 (1964).
xenograft tissue to underexpress or eliminate 4. Starzl, T.E. et al. Transplantation 2, 752–776 (1964).
the expression of such antigens, coupled with xenotransplantation in 5. Persidis, A. Nat. Biotechnol. 16, 882–883(1998).
tolerance conditioning of the recipient by 6. Auchincloss, H., Jr and Sachs, D.H. Ann. Rev.
the limelight as a Immunol. 16, 433–470 (1998).
chimeric or genetically engineered bone 7. Xiao, F. et al. Transplantation 58, 828–834 (1994).
marrow, will help overcome these difficul- technology to watch. 8. Fishman, J.A. Xenotransplantation 1, 47–57 (1994).
9. Murphy, F.A. Science 273, 746–747 (1998).
ties19. The future will continue to see innova- 10. Starzl, T.E. et al. Lancet 341, 65–71 (1993).
tions such as modifying xenograft organs by 11. Groth, C.G. et al. Tranplant. Proc. 28, 538–539
gene therapy approaches to improve the organs for transplantation, but has a long (1996).
© 2000 Nature America Inc. • http://biotech.nature.com
12. Deacon, T. et al. Nat. Med. 3, 350–353 (1997).
immune characteristics, efficiency and there- way to go before it is an accepted and even 13. Xue, Y.L. et al. Artif. Cells. Blood Substit. Immobil.
fore longevity of these organs and their routine clinical therapy. What makes it Biotechnol. 28, 337–345 (2000).
14. Ildstad, S.T. Lancet 347, 761 (1996).
hosts20. attractive is that it potentially obviates the 15. Cozzi, E. et al. Transplantation 70, 15–21 (2000).
Finally, both the US and the UK are pro- agonizing and uncertain wait for organs, and 16. Bracy, J.L. et al. Science 281, 1845–1847 (1998).
ceeding with the establishment of oversight also that it offers potential treatments for 17. Kobayashi, N. et al. Transplant Proc. 32, 1123–1124
(2000).
groups and guidelines to monitor and regu- currently intractable degenerative disorders. 18. Aomatsu, Y. et al, Transplant Proc. 32, 1071–1072
late clinical trials, as well as to continue and The concept has generated a great deal of (2000).
19. Cooper, D.K. Xenotransplantation 5, 6–17(1998).
increase the public debate over the risks healthy skepticism with regard to the poten- 20. Dyer, M.R. & Herrling, P.L. Mol. Ther. 1, 213–224
posed by the procedure. tial risks for novel infections. Efforts are (2000).
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