August 10, 2017

expert reaction to study on the use of genome editing to inactivate endogenous retroviruses in pigs

A study published in the journal Science looks at the use of genome editing to inactivate endogenous retroviruses in pigs.

Prof Darren Griffin, Professor of Genetics, University of Kent, said:

 “This represents a significant step forward towards the possibility of making xenotransplantation a reality.  The chance of transmitting PERV from the pig organ to the human cells was a significant barrier and the study shows yet another application of the CRISPR-Cas9 system.  By comprehensively demonstrating that PERV is the problem that we suspected that it may be, then providing a solution, the authors present a very elegant study. However, there are so many variables including ethical issues to resolve before xenotransplantation can take place. There may also be applications in agriculture for this work.”

Prof Ian McConnell, Emeritus Professor of Veterinary Science, University of Cambridge, said:

“Successful transplantation of tissues  and organs from animals to man, known as xenotransplantation,  has been one of the goals of modern medicine for the last 20 years.  It has been seen as an important strategy to overcome the chronic shortage of human organs for transplantation in man. There are several medical procedures using pig tissues such as heart valves in cardiac surgery, insulin producing pancreatic cells to correct diabetes in man and corneal transplants which have been used safely in man for many years. The safe use of pig organs such as kidneys in xenotransplantation has been seen as an approach which could be used to overcome the shortage of donor organs in human transplantation. The use of human organs for transplantation only meets a small percentage of the total and growing number of  individuals in desperate need of organ transplantation. It is a huge unmet need of modern medicine. But the use of animal organs such as pig kidneys and hearts is not without serious ethical and biosecurity concerns.

“There are three major obstacles that have prevented xenotransplantation becoming a clinical a reality: immunological rejection of the organ transplant  both acute and long term by the recipient’s exposure to pig antigens;  physiological incompatibility in terms of organ function; and the very real risk of transmission of pig cancer viruses or retroviruses from pigs into man.  This has been a major biosecurity concern which has prevented pig–to–man transplantation

“The problem is that all pig cells carry cancer viruses embedded in their DNA . These are known as endogenous retroviruses which although normally silent can be activated to become fully infectious for human cells when pig cells carrying these retroviruses are co-incubated with human cells. Since xenotransplantation involves long term intimate cell-to-cell contact the potential for the species jump of retroviruses for the entire life-time of the transplants is a very real one.

“In this paper novel gene editing techniques which had been previously used to inactivate the endogenous retroviruses in pig cell lines were combined with embryo manipulation to create live pigs whose retroviral genes have been inactivated or switched off.  It is suggested by this work that organ tissues from pigs carrying the inactivated viruses could be safely used to provide a source of cells , tissues and animals that in are genetically incapable of transmitting retroviruses in cell and organ transplants. This is envisaged as a novel strategy to overcome the biosecurity issue.

“At this stage this work provides a promising  first step in the development of genetic strategies for creating  strains of pigs where the risk of transmission of retroviruses in vivo organ transplantation has been eliminated. It remains to be seen whether these results can be translated into a fully safe strategy in organ transplantation.  Even if organs from these  gene-edited pigs could be safely used to overcome  virus transmission there remain formidable obstacles in overcoming immunological rejection and physiological incompatibility of pig organs in humans. The human immune system rejects foreign tissues as readily as it overcomes infections. Although immunosuppressive drugs  can be used to limit immune mediated rejection their use in experimental xenotransplantation in primates has so far been a failure. Human stem cell therapy where there will be limited rejection of the cells or tissues has the potential to be an alternative and more promising development.”

* ‘Inactivation of porcine endogenous retrovirus in pigs using CRISPR-Cas9’ by Niu et al. will be published in Science at 19:00 UK time on Thursday 10 August, which is also when the embargo will lift. 

The SMC also produced a Factsheet on genome editing which is attached and available here: http://www.sciencemediacentre.org/genome-editing/

Declared interests

Prof Darren Griffin: No conflicts of interest.

Prof Ian McConnell: No conflicts of interest.