Development of Genetically Engineered Pig Organs

Introduction

  In the United States, an average of 21 people die per day waiting for a transplant ¹. Due to the shortage of human organs, biotechnology companies have been looking for alternatives. Xenotransplantation, the process of transplanting tissues or organs of different species into humans, is one of them. Revivicor is focusing on genetically engineering pigs for xenotransplantation.

The main barrier for xenotransplantation is rejection. One cause of rejection is due to alpha 1,3 galactosyltransferase, an enzyme present in most animals except for humans and primates. When a tissue containing this enzyme is grafted into a human, the body’s immune system signals an attack causing a hyperacute rejection ². To overcome this barricade, Revivicor knocks out the gene that produces alpha 1,3 galactosyltransferase then clones pigs from the modified cells.

Figure 1. Revivicor’s xenograft process. [http://www.revivicor.com/technology.html]

Company History

 Formed in 2003 by David Ayers and based in Virginia, Revivicor is a regenerative medicine company that concentrates on genetically modifying pigs to be used as a tissue source for treatment of degenerative diseases in humans. The company is a spin-out of PPL Therapeutics, a UK company that produced Dolly the Sheep: the first cloned animal. Revivicor built upon the PPL Therapeutics’ technology and became the first company to clone a genetically-engineered pig.

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 In 2009, a study was run on primates induced with diabetes to test the viability of hCD46 transgenic porcine islets, acquired from Revivicor. After a 3-month follow-up, four of five monkeys experienced graft survival and insulin‐independent normoglycemia. The fifth monkey, selected at random and studied for more than a year.  …  The study marked the first time a functional islet xenograft in a diabetic monkey survived over a year³. The pigs that produced the hCD46 transgenic porcine islets had CD46 added and the pig gene alpha-GAL deleted. CD46 is a protein produced by a human gene, that aids in suppressing an immune attack on the transplanted cells⁴. Alpha-GAL epitopes trigger an immune response that results in rejection of the transplanted organ or tissue into primates. By removing alpha-GAL, the transplant is less likely to be rejected as well as degrade⁵.

Revivicor was purchased for approximately $8 million in 2011 by United Therapeutics Inc., and now operates as a subsidiary under the company. United Therapeutics is a biotech company that focuses on aiding rare and life-threatening diseases. The company was founded by Martine Rothblatt, who strives to create an endless supply of transplantable organs⁶. In 2014, $50 million was invested in Synthetic Genomics by Rothblatt. The company designs and inserts genetic add-ons into pig cells, which Revivicor uses cloning to produce pigs from the cells ⁶.

The National Heart, Lung, and Blood Institute in Bethesda, Maryland implanted a pig kidney, genetically engineered by Revivicor, into a baboon.

Conclusions

 Revivcor is still in business today but faces stiff competition: eGenesis, a company using CRISPR/Cas9 to genetically modify pigs for xenotransplantation. This technology allows eGenesis to more quickly and precisely edit the genes. The Cambridge, MA company is working on two different designs that they plan to combine into one pig cell, a pig with a humanized immune system and a pig wiped of viruses ⁷. The cell will then be cloned into a pig, the same process used by Revivicor.

 The Food and Drug Administration (FDA) may cause some setbacks to Revivicor as well. At the moment, the FDA suggests that xenotransplantation only be available to individuals with life-threatening diseases. With a majority of serious epidemics initiating from animal pathogens that have jumped to humans, the FDA is concerned with the possibility of disease from PERVs in the transplanted animal organs and tissues. Aside from the concern for disease, another hurdle to face is the regulations on genetic engineering. For a pig organ or islet to be able to go to market, the process in which the animal was genetically engineered must be approved⁸.

 Even with these roadblocks, the CEO of United Therapeutics is pushing Revivicor to engineer transplantable pig lungs and have plans in the pipeline to create xenotransplantable kidneys, hearts, and lungs by 2029.

References

1. Hansman H. The Future of Animal-to-Human Organ Transplants. 2015. https://www.smithsonianmag.com/innovation/future-animal-to-human-organ-transplants-180956402/. Accessed November 12, 2018.

2. Phelps CJ, Koike C, Vaught TD, et al. Production of alpha 1,3-galactosyltransferase-deficient pigs. Science (New York, NY). 2003;299(5605):411-414.

3. Van der Windt DJ, Bottino R, Casu A, et al. Long-term controlled normoglycemia in diabetic non-human primates after transplantation with hCD46 transgenic porcine islets. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2009;9(12):2716-2726.

4. Roth M. Can pig pancreas help cure diabetes? 2009. http://old.post-gazette.com/pg/09338/1018307-114.stm#ixzz0mOsOvbzG. Accessed November 11, 2018.

5. Park S, Kim W-H, Choi S-Y, Kim Y-J. Removal of alpha-Gal epitopes from porcine aortic valve and pericardium using recombinant human alpha galactosidase A. Journal of Korean medical science. 2009;24(6):1126-1131.

6. Regalado A. Surgeons Smash Records with Pig-to-Primate Organ Transplants. 2015. https://www.technologyreview.com/s/540076/surgeons-smash-records-with-pig-to-primate-organ-transplants/. Accessed November 7, 2018.

7. Weintraub K. CRISPR May Speed Pig-to-Human Transplants. 2017. https://www.technologyreview.com/s/603857/crispr-may-speed-pig-to-human-transplants/. Accessed November 13, 2018.

8. Reardon S. New life for pig-to-human transplants. Nature News. 2015;527(7577):152.