June 25, 2024

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Breakthrough: Pig Kidney Transplants Survive Two Years

Breakthrough: Pig Kidney Transplants Survive Two Years



Breakthrough: Pig Kidney Transplants Survive Two Years.

On November 27, 2015, George Church and Yang Luhuan, among others, published a paper in the journal Science [1], utilizing CRISPR-Cas9 gene-editing technology to remove endogenous retrovirus genes from the pig genome, clearing a major obstacle for using pig organs in human transplants and reigniting confidence in xenotransplantation.

In the same year, George Church, Yang Luhuan, and their colleagues founded the xenotransplantation company eGenesis, with the aim of addressing the global organ shortage.

On September 22, 2017, George Church, Yang Luhuan, and their team published a paper in Science [2], successfully cloning the world’s first batch of pigs with inactivated endogenous retroviruses, marking a significant step forward in xenotransplantation research. Following this, Yang Luhuan returned to China and established Qihan Biotech in Hangzhou, dedicated to innovating cellular and organ therapies through high-throughput gene editing technology and recipient-compatible modification of transplant immunity.

On January 10, 2022, and September 20, 2023, the University of Maryland School of Medicine completed two gene-edited pig heart transplants into humans. The former patient passed away two months after the transplant, while the latter is in good condition post-transplant. Both of these transplants were carried out under the FDA’s “compassionate use” program and involved hearts from pigs edited at ten different genetic loci.

 

 

On October 11, 2023, researchers from eGenesis published a study titled “Design and Testing of a Humanized Porcine Donor for Xenotransplantation” in Nature. This research documented the surgical design and successful process of transplanting genetically engineered pig kidneys into non-human primates (NHPs).

The pig underwent up to 69 gene edits, including the removal of three genes related to the synthesis of galactose antigens associated with hyperacute rejection, the insertion of seven human genes involved in regulating immune response pathways (inflammation, innate immunity, coagulation, and complement), and the elimination of endogenous retrovirus genes from the pig genome.

Combined with immunosuppressive therapy, these genetically engineered pig kidneys extended the survival of rhesus monkeys for over two years (758 days) post-transplant. This research highlights the potential of pig organs for human xenotransplantation and may further drive gene-modified pig organs into clinical trials.

 

Breakthrough: Pig Kidney Transplants Survive Two Years

 

On December 23, 1954, the United States conducted the world’s first successful human organ transplant. Since then, organ transplant technology has rapidly evolved, making it a viable option for patients with kidney failure and other organ diseases since the 1970s.

According to the World Health Organization (WHO), approximately two million people worldwide require organ transplants each year. However, the major obstacle for these patients is not technical but the severe shortage of organ donors, with a global average organ supply-to-demand ratio of less than 1:20. In the United States, for instance, there are currently 114,000 people waiting for organ transplants, while only 30,000 receive them each year. On average, more than 20 people die each day while waiting.

Researchers worldwide are exploring various approaches to address the organ shortage issue, and one with significant promise is xenotransplantation. Xenotransplantation involves using organs from different species for human transplantation.

Early xenotransplantation research primarily focused on obtaining organs from non-human primates. For example, in 1984, cardiologist Dr. Leonard L. Bailey performed the groundbreaking xenotransplantation of a baboon heart into a newborn named Fae. Fae was born with a severe heart malformation, and at the brink of death, Dr. Bailey conducted this world-changing procedure. Unfortunately, it didn’t save Fae, who passed away 21 days after the surgery due to organ rejection and failure.

In recent years, scientists have turned to pigs as a source for xenotransplantation. Pigs are commonly raised as a food source for humans, which poses fewer ethical concerns when using their organs. Additionally, pigs have large litters, short gestation periods, and organ sizes similar to humans, making them an ideal source for human organ transplantation.

However, transplanting pig organs into humans requires overcoming several challenges, including organ rejection and the risk of zoonotic diseases (transmitting pig viruses to humans). Previous research identified three galactose antigens in pigs that can be recognized and attacked by human antibodies, leading to organ rejection. Furthermore, endogenous retroviruses in pigs have been identified as a significant risk in human transplantation.

In this latest study, the research team used Yucatan miniature pigs as donor pigs and conducted up to 69 gene edits, including the removal of three genes responsible for antigen expression that can cause rejection (GGTA1, CMAH, and B4GALNT2L). They also introduced seven human genes to reduce the immune system’s response in non-human primates, including complement-related CD46 and CD55, coagulation-related THBD and PROCR, innate immunity-related CD47, and inhibitors of ischemia-reperfusion injury, apoptosis, and inflammation TNFAIP3 and HMOX1. An additional 59 gene edits inactivated all copies of retroviral genes in the pig genome.

 

Breakthrough: Pig Kidney Transplants Survive Two Years

 

The genetically modified pig kidneys significantly prolonged the survival time of transplanted rhesus monkeys, reaching up to 176 days, compared to only 24 days for pig kidneys with the removal of the three antigen-expressing genes. This suggests that the introduced human genes can, to some extent, prevent rejection. When combined with immunosuppressive therapy, pig kidneys provided long-term survival of 758 days for the rhesus monkeys.

 

Breakthrough: Pig Kidney Transplants Survive Two Years

 

 

Functional analysis in vitro showed that endothelial cells in the edited pig kidneys regulated inflammation in a way that mimicked human endothelial cells. This suggests that the edited cells acquired a high level of compatibility with the human immune system. Furthermore, the evaluation of biomarkers for stable transplant recipient kidney function indicated that a single transplanted pig kidney provided sufficient metabolic filtering to compensate for the absence of two natural kidneys.

This milestone preclinical data in xenotransplantation demonstrates that gene-edited pig kidneys can survive long term after xenotransplantation and maintain organ function for over two years when transplanted into non-human primates. These results indicate a promising future for pig organ transplantation into humans and further advance the technology into clinical trials.

Dr. Mike Curtis, CEO of eGenesis, stated, “We have successfully increased post-xenotransplantation survival from months to years, offering new hope for tens of thousands of patients in need of life-saving organ transplants with our human-compatible organs (HuCo™).”

This research data will also support the clinical development of eGenesis’ main pipeline, pig kidney xenotransplantation (EGEN-2784), and their efforts in advancing ex vivo liver perfusion and heart transplant projects, as well as islet cell transplant projects.

 

Breakthrough: Pig Kidney Transplants Survive Two Years

References:

  1. Link to Paper 1
  2. Link to Paper 2
  3. Link to Paper 3
  4. eGenesis Pipeline

(source:internet, reference only)


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