Xenotransplantation, Safety and Ethical Issues

• Xenotransplantation: Transplantation of tissue from one species to another
• Allotransplantation: Transplantation of tissue from one individual to another within a given species

Types of Xenotransplantation

• Cell Transplants
  Islets
  Fetal neural
• Ex vivo Organ Assist
  Liver
• Solid Organ Transplants
  Heart
  Kidney

Non-human Primates as Donors

Breeding Issues

• Long <!g>gestation period
• Single births
• Lack of controlled environment

Ethical Issues

• Non-human primates are genetically more closely related to humans

Potential Health Risks

• Infectious <!g>viruses

Regulatory Update

• FDA Issued Guidelines for Comments in April 1999: Guidance for Industry – Public Health Issues Posed by the Use of Non-human Primate Xenografts in Humans”

  Non-human primate donors for xenotransplantation cannot be proposed for clinical use until scientific research and evaluation can identify risks associated with such transplant protocols.

Pigs as Organ Donors

Breeding Issues

• Short gestation period
• Born in litters
• Barrier facilities established

Ethical Issues

• Over 93 million pigs per year in the US are slaughtered for food

Potential Health Risks

• Exogenous viruses: eliminated by raising in barrier facilities
• Endogenous retroviruses: no pathogens identified

Advantage of Inbred Miniature Swine

• MHC Inbred and <!g>Recombinant Lines are Available
• Twenty-five Years of Breeding and Medical History
• Physiology Similar to that of Humans
• Transplantation Technology Available Including Species Specific Cytokines and Antibody Reagents
• Model Consistent with Clinical Findings

Scientific Issues Associated with Xenotransplantation

Two Major Hurdles

• Humans have naturally occurring antibodies which react with carbohydrates on the surface of pig cells
• The human immune response to xenogeneic tissue is very strong and difficult to manage

Major Scientific Approaches to Achieving Xenotransplantation

• Develop Specific Immune Tolerance
• Genetically Engineer Pigs

Ethical Issues Associated with Xenotransplantation

• Use of Animal Organs
• <!g>Genetic Engineering of Pigs
• Potential Health Risks

Potential Health Risks

• Risks to the Patient
• Risks to Society

Risks to the Patient

• Allotransplants
  HIV, Hepatitis, CMV
• Xenotransplants
  PERVs, unknown viruses

Risks to Society

• Potential for Recombination Among Pig and Human Retroviruses to Form Pathogenic, Infectious Strains
• Potential for Emergence of Unknown Zoonosis

What Can Be Done to Manage Risks?

• Identify and Characterize PERVs
• Develop Assays to Monitor Infection
• Acquire and Test Samples
  From individuals with long-term exposure to pigs or pig products, such as pig farmers
  From burn patients who had pig skin transplants
• Perform Carefully Controlled and Well Monitored Clinical Studies in a Limited Number of Individuals