August 12, 2017
Scientists have edited the pig genome to deactivate a family of retroviruses, and the results hold important implications for transplant medicine in people.
According to the American Association for the Advancement of Science (AAAS), which published the findings in its journal Science, the shortage of human organs and tissues for transplantation represents one of the most significant unmet medical needs.
One promising prospect is to use animal organs in humans, and pig organs are particularly compatible for such transplantation, which is known as xenotransplantation. However, the pig genome includes porcine endogenous retroviruses (PERVs), which can be passed on to other cells when cultured together.
Gene editing techniques could prove useful for removing virus genes from the pig genome, paving the way for pig-to-human transplants, yet efforts so far have only been successfully demonstrated in cell lines, not live animals, AAAS said.
Biotechnology company eGenesis, which focuses on transforming xenotransplantation into a life-saving medical procedure, announced the publication of the study.
The eGenesis scientists and their collaborators demonstrated the inactivation of PERV to prevent cross-species viral transmission and a breakthrough in producing the first PERV-free pigs -- an important milestone for xenotransplantation, the company said.
“This is the first publication to report on PERV-free pig production,” said Dr. Luhan Yang, co-founder and chief scientific officer of eGenesis. “We generated a protocol to enable multiplex genome editing, eradicated all PERV activity using CRISPR technology in cloneable primary porcine fibroblasts and successfully produced PERV-free piglets. This research represents an important advance in addressing safety concerns about cross-species viral transmission. Our team will further engineer the PERV-free pig strain to deliver safe and effective xenotransplantation.”
This study examined the risk of PERV infectivity and demonstrated in vitro that PERVs infected human cells and were transmitted to human cells that had no history of contact with porcine cells in the co-culture condition, substantiating the need to address this issue in order to ensure safe xenotransplantation practice.
Researchers developed a strategy to enable efficient and precise genome editing in primary cells using CRISPR-Cas9 technology. In conjunction with a method to inhibit primary cell death during multiplex genome editing, the researchers successfully produced viable, PERV-free porcine embryos via somatic cell nuclear transfer using engineered primary cells, eGenesis said.
They then implanted the PERV-free embryos into surrogate sows and demonstrated the absence of PERV re-infection, initially in fetuses and, finally, in recently born piglets. These piglets are the first animals born free of endogenous virus and will be monitored by the eGenesis team for any long-term effects.
The eGenesis team, having produced the first piglets free of active PERVs, is working toward combining the safety benefits of PERV-free pigs, with additional gene editing addressing the immunological response to increase organ immune and functional compatibility.
CRISPR (clustered regularly interspaced short palindromic repeats) is a genome editing tool that can selectively delete, modify or correct a disease-causing abnormality in a specific DNA segment. CRISPR technology uses a protein-RNA complex composed of either the protein Cas-9 or Cpf1, each of which binds to a guide RNA (gRNA) molecule that has been designed to recognize a particular DNA sequence.
Dr. Adam Griesemer, director of the Large Animal Xenotransplantation Laboratory at New York-Presbyterian/Columbia University Medical Center's Columbia Center for Translational Immunology, who was not involved in the study, noted that "the production of a pig from the edited genome is a difficult process, and the fact that researchers were able to do that is a big step forward. It will still be challenging to further modify the genome of that animal to express either human proteins that can protect an organ after transplant or to remove certain pig proteins or carbohydrates that could be targets of organ rejection. Each advancement of any of the groups working in xenotransplantation brings us that much closer to the successful clinical application of the technology.”
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