Xenotransplantation is the transfer of living cells, tissues and/or organs from non-human animal species into humans (although technically, it could be the other way around or between any two species.
Why is xenotransplantation important?
There is a worldwide shortage of supply of organs for clinical transplantation, and many people die waiting for organs to become available. The development of xenotransplantation can be seen as serving several purposes: to be a complete substitute for human organs; to supplement human organs, thus easing the current shortage available for transplantation; or to be a "bridge" organ before a "destination" organ can be found. As well as xenotransplantation's value to patients, there are also high stakes for others concerned, such as scientists, the biotechnology industry and infectious disease specialists.
Xenotransplantation is currently not a recognized medical practice in industrialized countries, but has the potential to encompass a broad spectrum of applications. Any disease that can be treated by human-to-human transplantation may be able to be treated by xenotransplantation. Cellular transplants could provide treatment for people with diabetes, Alzheimer's or Parkinson's diseases. Tissue xenotransplantations could include skin grafts for burn patients, corneal transplants for the visually impaired or bone transplants for reconstructing limbs. Organ xenotransplantation could include whole hearts, lungs, livers, kidneys or pancreases.
Recent advancements in understanding hyperacute transplant organ rejection suggest that it may someday be possible to chemically and genetically modify cells, tissues and organs from other species to minimize the risk of serious rejection or xenosis - see below.
Xenosis (also called xenozoonosis)
Xenosis is the infection of humans by agents such as bacteria or viruses that are derived from animals. The infection may or may not result in symptoms of human disease. The possibility of xenosis raises questions about the safety of using xenotransplantation in individuals, but it could also potentially place the general public at risk. The worst-case scenario could be a major new epidemic. This potential threat to public health lies at the heart of the debate about the safety of xenotransplantation.
Blood clotting around xenotransplants is also of concern, and they too must be stopped if the new organ is to live.
Another scientific concern is uncertainty whether xenotransplantation will work or whether high levels of immunosuppression will leave patients open to more frequent infectious diseases or cancer.
The body's immune system uses several lines of defence against foreign organisms like parasites and bacteria. This would include defence against transplanted tissues, cells and organs that are not normally seen in a human body. Thus, the risk of rejection in xenotransplantation primarily involves the immune system attacking the transplanted tissue and not recognizing it. Scientists have been trying various methods to overcome this phenomenon. Some of these procedures involve trying to alter the patient's immune system to increase its tolerance to transplanted tissues, cells or organs; for example, altering the recipient's immune system and immune cells so that there is no immune response to the foreign transplant or interrupting communications so that no immune response is initiated. Others use genetic engineering to change the cells, tissues and organs of the donating animal, especially by deleting certain animal genes and replacing them with human genes.
What animals may be suitable donors?
It is thought that even though non-human primates, such as apes or baboons, are genetically closest to humans, the transfer of infective agents could be more likely between closely related species. Thus, the transplant animal of choice is becoming the pig. Their organs are the most comparable in size to adult human recipients, they have large litters, they quickly grow to maturity and they can be raised solely for transplantation purposes in clean environments, and they may pose less risk of infection to humans than non-human primates. However, some new pig endogenous retroviruses, which could be very difficult to eradicate, have been shown to infect human cell lines in vitro, and this is still causing concern.
Medical science already uses animal parts for various therapeutic reasons, such as replacement heart valves from pigs. However, these products have been chemically treated - they are not functional, living tissue. This makes them different from the living cells, tissues and organs used in xenotransplantation.
Regulatory status in Canada
Xenotransplantation is currently not prohibited in Canada. However, the live cells, tissues and organs from animal sources are considered to be therapeutic products (drugs or medical devices) in Canada. Thus, xenotransplantations are subject to the requirements of the Food and Drugs Act, the Food and Drug Regulations or the Medical Devices Regulations. To conduct a human clinical trial, a sponsoring company or research institute would have to apply to Health Canada for approval before proceeding. No clinical trial involving xenotransplantation has yet been approved by Health Canada.
Regulatory status in other countries
The US Food and Drug Administration has updated its 1996 Public Health Service Guidelines for Infectious Disease Issues in Xenotransplantation. It has also approved clinical trials involving xenotransplantation.
In Great Britain, clinical trial applications may be submitted to the United Kingdom Xenotransplantation Interim Regulatory Authority (UKXIRA). Established in 1997, UKXIRA has received no clinical trial applications to date.
The World Health Organization (WHO) hosted a consultation with international experts and published guidelines in 1998 on preventing and managing infectious disease associated with xenotransplantation.
In 1999, the Council of Europe's Parliamentary Assembly called for a moratorium until the technology is evaluated and guidelines are established. The Assembly also asked the Council of Europe Public Health and Bioethics Committees to work with the WHO on a strategy which balances ethical, medical, scientific, legal, social and public health issues before human clinical trials continue.
According to the Organisation for Economic Co-operation and Development (OECD), limited clinical trials involving xenotransplantation are planned or ongoing in some countries, such as the United States, Belgium, Spain and Germany.
What has Health Canada done to address the issue of xenotransplantation in Canada?
November 1997 - Health Canada sponsored a National Forum on Xenotransplantation - Clinical, Ethical, and Regulatory Issues. Several important recommendations resulted from this forum, such as the need to inform and involve the public on issues related to xenotransplantation, and the need to develop safety standards that can be used to regulate xenotransplants, if and when they are approved for use in Canada. Health Canada established an Expert Working Group on Xenotransplantation Standards to develop the safety standards.
July 1999 - As a result of the work of the Expert Working Group, Health Canada released for public comment the draft Proposed Canadian Standard for Xenotransplantation. Although not presently referenced in legislation or regulations, it addresses certain xenotransplantation-specific areas not covered by the current regulatory framework. It includes some performance requirements aimed at preventing disease transmission and assuring optimal clinical performance of xenografts, as well as standards for animal production, care and disposal. Health Canada has recently initiated a project to update this proposed standard.
February 1999 - Health Canada issued A Notice to Interested Parties: Intent to Develop a Regulatory Framework for Xenografts, followed in March 1999 by A Notice to Hospitals: Clinical Use of Animal Cells, Tissues or Organs to Treat Patients. These notices communicated: 1) the current federal regulatory requirements about the clinical use of xenotransplantations, 2) Health Canada's intent to develop appropriate regulations for xenotransplantations, and 3) that applications under the Special Access Program (SAP) of Health Canada for the use of xenotransplants are not being considered. The SAP provides access to non-marketed drugs for practitioners treating patients with serious or life-threatening conditions when conventional therapies have failed, are unsuitable, or unavailable. The SAP authorizes a manufacturer to sell a drug that cannot otherwise be sold or distributed in Canada.
Fall 1999 - An Expert Advisory Committee on Xenograft Regulation was formed "to provide Health Canada with timely advice on medical, scientific, ethical and communication issues related to the regulation of xenografts."
March 2000 - Health Canada sponsored a Xenotransplantation Surveillance Workshop, which brought together infectious disease and other experts to discuss issues concerning xenotransplantation surveillance in Canada.
April 2000 - In response to recommendations identifying the need for public consultation, Health Canada developed a Public Involvement Plan for xenotransplantation and sponsored a Planning Workshop to obtain input to the plan. As a step toward implementing the plan, Health Canada funded the Canadian Public Health Association to form a Public Advisory Group and to conduct a public consultation on xenotransplantation. The report arising from this initiative was released to Health Canada and to the public in January 2002.
Canada's involvement in xenotransplantation discussions has not been limited to the national scene. Canada is a member country of the OECD and has participated in OECD-sponsored workshops discussing surveillance of infection following xenotransplantation. Health Canada, together with the WHO, initiated an Electronic Discussion Group on International Xenotransplantation Policy Considerations to provide a forum for global discussions on xenotransplantation public policy consideration. Health Canada is also represented as an observer on the Council of Europe's Working Party on Xenotransplantation, which prepared a report on the state of the art in the field of xenotransplantation in 2003. Health Canada has also participated in workshops sponsored by the Secretary's Advisory Committee on Xenotransplantation of the US Food and Drug Administration.
Consultations to hear the views and concerns of Canadians have been ongoing at several levels. Various stakeholders and the Canadian public have been provided with the opportunity to participate in the issue identification exercise through a variety of consultations, as described above. Between fiscal years 2000 and 2002, the Public Advisory Group, formed by the Canadian Public Health Association and funded by Health Canada, conducted a public consultation on issues related to xenotransplantation and reported on their results. The final report, Animal-to-human transplantation: Should Canada proceed?, summarized key findings. These included "That Canada not proceed with xenotransplantation involving humans at this time as there are critical issues that first need to be resolved." Following the release of this report, Health Canada established a Working Group to develop a common understanding of the key issues in policy development process for xenotransplantation. The Working Group also benefitted from the contribution of an external bioethics advisor.
As Health Canada continues analysis on these issues, the need to update the Draft Standard for Xenotransplantation has been identified. This exercise has been initiated.
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