Xenotransplantation
December 6-7, 1999 · Boston Park Plaza Hotel · Boston, MA
It has been predicted that the market for animal and artificial organ transplants is expected to be worth more than $10 billion annually by the year 2005. (U.S. Artificial Organ Transplant Markets, Frost & Sullivan, April 26, 1999) As clinical breakthroughs come to fruition and new scientific data becomes available, it is imperative that your company or institution keeps informed. IBC's 5th Annual Xenotransplantation Conference is an international event that brings together researchers, executives and clinicians from academia and industry to address issues/topics such as xenozoonoses, rejection and clinical trials.
Hear From These Industry Leaders:
Alexion Pharmaceuticals
BioHybrid Technologies, Inc.
BioTransplant, Inc.
Diacrin, Inc.
Nextran, Inc.
PPL Therapeutics, LLC
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Agenda for Xenotransplantation
December 6-7, 1999 · Boston Park Plaza Hotel · Boston, MA
Pre-Conference Workshop - Monday, December 6, 1999
| PRE-CONFERENCE WORKSHOP| DAY ONE| DAY TWO|
Xenozoonoses: Microbiological Safety & Diagnostics
7:30 Workshop Registration, Poster/Exhibit Set Up and Coffee
8:30 Chairperson's Welcome and Opening Remarks
Jonathan S. Allan, D.V.M., Scientist, Department Virology & Immunology, Southwest Foundation for Biomedical Research
8:45 Retroviral Dynamics in the Non-Human Primate Host: A Model for Understanding Viral Transmission in the Xenotransplant Setting
Jonathan S. Allan, D.V.M.
Retroviral infections may pose serious risks to the immunosuppressed xenograft recipient due to their persistence and variable nature of disease. The natural history and epidemiology of simian retroviruses in baboons can represent important areas for understanding determinants of pathogenicity and transmissibility, both of which are critical factors in gauging public health risks in xenotransplantation.
9:15 Pig Endogenous Retrovirus Distribution in a MHC Inbred Herd of Miniature Swine
Clive Patience, Ph.D., Principal Scientist, BioTransplant Incorporated
The possible introduction of infectious agents into the recipient of a transplant is a safety concern for both allotransplantation and xenotransplantation. Pig endogenous retroviruses (PERV) are considered a risk of using porcine tissue for xenotransplantation.
PERV transmission studies from primary cells of a MHC inbred miniature swine herd, and the identification of novel PERV families in the genomes of the pigs will be presented.
9:45 Refreshment Break and Poster/Exhibit Viewing
10:30 Strategies for Surveillance of PERV Infection
Walid Heneine, Ph.D., Chief, Molecular Epidemiology and Zoonoses Section, HIV and Retrovirology Branch, Centers for Disease Control and Prevention
Recipients of pig xenografts will inevitably be exposed to the pig endogenous retroviruses (PERV). Both molecular and serologic methods for laboratory surveillance of PERV infection will be described. Strategies for distinguishing PERV infection from microchimerism will also be highlighted. Data from PERV surveillance will be presented.
11:00 Biological Characterisation of Porcine Endogenous Retroviruses and Specific Diagnostics
Joachim Denner, Ph.D., Scientific Director, Paul-Ehrlich-Institute, Head, German Working Group Xenotransplantation, Germany
Porcine Endogenous retroviruses (PERVs) replicate in human cell lines and primary cells. PERV has been purified and characterized biochemically and immunologically. Antibodies against all major viral proteins have been obtained and specific diagnostics based on peptide ELISAs and Western blot assays using purified and recombinant viral proteins, as well as immunochemistry have been developed. These diagnostics have been used for screening of humans and animals exposed and not exposed to PERV and they could be used for monitoring xenotransplantation patients. These diagnostics have also been used for screening the host range of PERV and the development of different animal models for the pathogenic consequences of PERV infection. Although PERVs have been shown to be immunosuppressive in vitro for human cells, it is unclear whether it replicates in vivo and whether it is pathogenic
11:30 Discussion of the Potential Infectious Disease Risks of Xenotransplantation
John S. Logan, Ph.D., Vice President, Research & Development, Nextran, Inc.
The possible transmission of infectious agents in pig to human xentoransplantation is a key safety concern. I will discuss various strategies to minimize this risk and present data on Nextran's experience with the development of a health specification for animal's that could be used as donors.
12:00 Close of Pre-Conference Workshop
Day One - Monday, December 6, 1999
| PRE-CONFERENCE WORKSHOP| DAY ONE| DAY TWO|
1:30 Main Conference Registration and Poster/Exhibit Set Up
2:00 Chairperson's Remarks
Jonathan H. Dinsmore, Ph.D., Senior Director of Cell Transplantation Research, Diacrin, Inc.
Session 1: Cloning Technologies
2:10 Cloning: Applications in Xenotransplantation and Cell Therapy
Robert P. Lanza, M.D., Senior Director, Tissue Engineering and Transplant Medicine, Advanced Cell Technology
Nuclear reprogramming in livestock species is now routinely possible in our own and other laboratories, and may soon be used to clone cells and organs for transplantation into patients suffering from a wide range of disorders that result from tissue loss of dysfunction.
In addition to patients with heart, liver, kidney and lung disease; over 8 million patients in the U.S. suffer from neurodegenerative disorders such as Parkinson's disease, over 17 million patients suffer from diabetes, and millions more from arthritis, AIDS, strokes and other diseases that may one day be treatable with cell transplantation. The ability to reset the life span of near senescent cells by nuclear transfer could enable us to carry out an unlimited number of gene targeting events. In addition to improving the safety of animal tissues (by knocking-out the genes for prions and certain retroviruses), this technology could be used to make universal donor cells, customized cells or animal organs that closely resemble human organs. Of particular interest is the potential of modifying genes involved in the immunological rejection of tissues after xenotransplantation.
Session 2: Rejection, Complement Inhibition & Immune Modulation
2:40 Tolerance in the Pig to Non-Human Primate Model
Michel Awwad, Ph.D., Director, Immunological Assays, BioTransplant Incorporated
Tolerance induction may be an essential component to successful clinical xenotransplantation due to the strength of the immune response. Specific tolerance can be induced using mixed hematopietic chimerism in a variety of small and large animal models of allogeneic and xenogeneic transplantation. Our collaborators and we have been adapting this model to the pig to baboon system as a preclinical proof of principle for xenotransplantation. The combination of mixed hematopoietic chimerism and specific immunabsorption of natural absorption of natural antibodies will be discussed.
3:10 Refreshment Break, Poster and Exhibit Viewing
3:55 HAR and Beyond: A Comprehensive Approach to Prevention of Xenograft Rejection
David Ayares, Ph.D., Vice President of Research and Development, PPL Therapeutics, Inc.
Advances in the targeted modification of porcine cells, procine nuclear transfer (cloning), complement regulation and tolerance induction, will be presented as part of PPL's comprehensive approach to modulation of the immune response against vascularized pig organs. Inhibition of hyperacute rejection (HAR) will be achieved via knockout of the -1,3 galactosyl transferase (GT) gene in specific, SLA-defined, somatic pig cells, followed by the use of those cells in somatic cell nuclear transfer. The -1,3 GT knockout pig will serve as the platform for strategies under development, aimed at modulation of delayed xenograft rejection (DXR), and T cell mediated xeno responses.
4:25 The Immunological Hurdles to Organ Xenotransplantation
Jeffrey L. Platt, M.D., Transplant Biology, Head of Section, Department of Surgery, Mayo Clinic Research during the past decade has clarified the nature of the immunological response to xenotransplantation and has suggested various therapeutic approaches that might be applied. One response involves anti-Gal 1-3Gal antibodies which trigger hyperacute and acute vascular rejection. Another involves intrinsic susceptibility to complement-mediated injury. These problems may be addressed by genetic and pharmacologic therapies. Another barrier to xenotransplantation is the elicited immune response. The nature and severity of this response remains a matter of controversy; however the need to devise effective therapeutic strategies is widely appreciated
4:55 Immunomodulation: Applications and Pitfalls for Cellular Transplantation
Denise Faustman, M.D., Ph.D., Associate Professor of Medicine, Director of Immunobiology, Massachusetts General Hospital, Harvard Medical School
Immunomodulation is the transplantation concept that the donor antigens of tissues may be manipulated prior to transplantation to deter host rejection. Over the past 10 years we have been working on this concept as a strategy to avoid graft rejection and frequently in the context of changing donor class I proteins. Donor class I antigens can be altered at the DNA or protein level and research data shows efficacy of these methods in murine, primate and recently in the human model of transplantation. Both the efficacy and limitations of these methods will be discussed as they relate to various transplantation settings.
5:25 Close of Day One
Day Two - Tuesday, December 7, 1999
| PRE-CONFERENCE WORKSHOP| DAY ONE| DAY TWO|
8:00 Poster/Exhibit Viewing and Coffee
8:30 Chairperson's Remarks
Julia Greenstein, Ph.D., Senior Vice President, Research Chief Scientific Officer, BioTransplant, Inc.
Session 3: Clinical Updates
- Cell Transplantation & Therapy -
8:40 Overcoming the Barriers to Engraftment of Porcine Hematopoietic Cells in Primates
Aron Thall, Ph.D., Associate Director, Glycobiology & Immunology, BioTransplant Incorporated
The successful establishment of tolerance through mixed hematopoietic chimerism in the pig to primate model is limited by a series of immunologic and physiologic barriers. We have conducted experiments to define the dominant barriers and have tested approaches to overcome them using both in vitro and mouse models. These procedures are now being used to ameliorate barriers in the pig to primate model.
9:10 Fetal Neural Cell Transplantation: Animal Models and Clinical Studies
Jonathan H. Dinsmore, Ph.D.
Fetal cell transplantation performed in over 200 patients to date resulted in significant disease reversal or to no improvement. The variability may in part be to difficulties in obtaining reliable tissue from aborted human fetuses. Diacrin is developing porcine fetal cells as an alternative to human fetal. Diacrin and Genzyme have multiple human clinical trials in progress, which will be discussed.
9:40 Treatment of Diabetes with Immunoisolating Microreactors
David E. Wolf, Ph.D., Vice President for Research and Development, Chief Scientific Officer, BioHybrid Technologies, Inc.
The immune system represents a formidable challenge to the promise of xenotransplantation. BioHybrid Technologies' microreactor immunoisolation system protects transplanted islets both from cell mediated immunity and the complement pathway. Data is presented showing the effectiveness of this system in providing immunoisolation for allografts transplanted into normal and autoimmune hosts and for discordant xenografts transplanted into normal hosts.
10:10 Refreshment Break, Poster and Exhibit Viewing
- Organ Transplants -
10:55 The Development of Transgenic Livestock for Clinical Applications
William L. Fodor Ph.D., Senior Director, Alexion Pharmaceuticals
Pig-to-primate xenotransplantation is now the object of intense research with the aim of solving the increasing shortage of organs for human transplantation and for developing new cell- and tissue-based therapies. Progress towards its clinical application has been precluded by a vigorous humoral immune response. Natural antibody reactivity and complement activation on the xenogeneic cell surface leads to hyperacute rejection of the transplanted cell or organ. Genetic engineering of donor cells and transgenic animals expressing human complement inhibitors such as hCD59 significantly delay the time of xenograft rejection. Strategies to decrease the natural antibody response have also been developed. Expression of human a1,2-fucosyltransferase (H transferase, HT) modifies the carbohydrate phenotype of pig cells resulting in reduced anti-Gala1,3-Gal antibody reactivity and human serum-mediated cytolysis. We have now developed transgenic pigs that co-express hCD59 and HT in various cells and tissues. Our data demonstrate that this combinatorial approach represents a significant step towards preventing hyperacute and delayed xenograft rejection and lead to the application of xenogenic cells, tissues and organs to clinical transplantation.
11:25 Human Clinical Trials in Xentoransplantation
Robert E. Michler, M.D., Professor and Chief, Cardiothoracic Surgery, Ohio State University Medical Center Clinical Studies have shown that acceptance of xenografts is obtainable. Results will be discussed. Experimental studies have demonstrated significant improvement in the survival of transplanted transgenic organs. Considerable interest on the part of transplant physicians, transgenic organ manufacturing companies and the government have led to a number of discussions as to the feasibility of human clinical trials in the near future. The experimental results that have prompted these discussions will be reviewed, as well as a summary of recent dialogue with federal agencies regarding human clinical trials. The timing of these human clinical trials remains uncertain and the perspective presented will review the pertinent issues that have evolved in his area since 1990.
11:55 Inhibiting Gal
1,3Gal (Gal) Antibody Production by B Cell Tolerance
Mary-Ann Campbell, Ph.D., Manager, Research, La Jolla Pharmaceutical Company
Hyperacute rejection of porcine-to primate xenografts is mediated by natural antibodies against Gal oligosaccharide determinants. We have explored pharmacological approaches that clear circulating Gal antibodies and tolerize the B cells that produce these antibodies. Recent studies in primates and transgenic mice indicate that multivalent conjugates of Gal can reduce Gal B cells in the spleen and circulating Gal antibody levels. The therapeutic potential of a B cell toleragen approach to hyperacute rejection will be discussed.
12:25 Question & Answer
1:00 Luncheon * Sponsorship Opportunities Still Available
FDA/NIH Colloquium
2:30 Moderator's Comments/Remarks
Jeffrey L. Platt, M.D.
2:45 Current FDA Policy on Xenotransplantation
Eda T. Bloom, Ph.D., Chief Laboratory of Cellular Immunology, Division of Cellular and Gene Therapies, Chair, FDA Xenotransplantation Action Plan, Food & Drug Administration
3:05 The Secretary's Advisory Committe on Xenotransplantation Amy Patterson, Ph.D., Director of Recombinant DNA Activities, National Institutes of Health
3:25 Open Panel Discussion
Take this opportunity to ask FDA/NIH Officials YOUR most pressing questions!
Sample Discussion Topics:
Pre-clinical and clinical applications
Xenotransplantation protocols
Regulatory Hurdles/Issue And More...
4:30 Close of Conference
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