Genetically Modified Pigs Could Ease Organ Shortage

Genetically Modified Pigs Could Ease Organ Shortage

Researchers breed animals whose organs may be compatible with humans

Genetically modified pigs produced by the National Swine Resource and Research Center for researchers at the University of Missouri. The researchers are studying the possibility of someday transplanting porcine islets made with the gene editing technology into people with diabetes as a possible treatment. PHOTO: MELISSA SAMUEL/THE NATIONAL SWINE RESOURCE AND RESEARCH CENTER; UNIVERSITY OF MINNESOTA

By AMY DOCKSER MARCUS
Updated Dec. 1, 2016 12:44 p.m. ET
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There are more than 120,000 people in the U.S. waiting for an organ transplant and not enough donors. The dire shortage has led some researchers to consider an unusual solution: They are breeding genetically modified pigs whose organs could be compatible for human transplant.

Researchers have been trying for decades to make animal-to-human transplants work, a process known as xenotransplantation. Pigs are a particularly promising source of organs. They produce big litters. Organs such as the kidney and liver are similar in size to those of humans. “Nobody has come up with a better animal,” says Joseph Tector, a professor of surgery who runs the xenotransplantation program at the University of Alabama at Birmingham.

Rewriting the CodeScientists can use the gene-editing technology called Crispr-Cas9 to manipulate pig gene expression to make the animals’ organs more compatible with humans. Here’s how it works:
1.

A chunk of RNA is programmed to look for a specific segment of DNA. It is paired with a natural protein called Cas9 taken from bacteria, where it functions as a genetic scalpel.

2.

Once inserted into a pig’s cell, the RNA/Cas9 combination looks for a DNA sequence that matches its RNA.

3.

When it finds a match, the Cas9 cuts both strands of the DNA

4.

Repair enzymes can fill and seal the gap in the DNA with new genetic information. This can be used to manipulate the expression of specific pig genes, making pig organs more compatible with human recipients.

Innovative Genomics Initiative; Matt Tector, University of Alabama-BirminghamJOHN GOULD / THE WALL STREET JOURNAL
A previous push into xenotransplantation by companies and scientists in the 1990s faltered due to a number of factors. In early experiments with nonhuman primates, their immune system attacked and rejected the pig organs. There were concerns that remnants of retroviruses in pigs’ genetic makeup, while harmless to the pigs, might end up infecting humans. Trying to modify the pig genome was a slow process; it often took years to successfully modify a single gene.

Then last year, a group led by George Church of Harvard University published a paper describing their use of a new gene-editing technology called Crispr-Cas9. Unlike previous gene-editing systems, Crispr allowed the researchers to make multiple changes simultaneously to inactivate viral remnants in the pigs’ genes.

Crispr has helped renew enthusiasm for xenotransplantation.

Luhan Yang, one of the authors of the paper and now president and chief scientific officer of EGenesis Bio, which she and Dr. Church co-founded, says the company has used Crispr to create pig embryos designed to keep human immune systems from rejecting them. They have also used Crispr to inactivate pig retroviruses. The researchers are gathering data and hope to have pigs next year whose organs can be tested in trials with animals.

“Patients are dying. I am sensitive to their urgency,” Dr. Yang said.

Earlier this year, the University of Alabama at Birmingham received a $19.5 million grant from United Therapeutics Corp., a biotech company in Silver Spring, Md., to establish a Xenotransplantation Institute and facility to make Crispr pigs.

Dr. Tector said he and collaborators previously used Crispr to create pigs with three genes knocked out that play a crucial role in why human immune systems reject a pig organ. He has preliminary data with pig kidneys transplanted into two rhesus monkeys; the longest lived more than a year.

More data and more experiments are needed, and potentially more modifications in the pigs are planned. Dr. Tector says they hope to start discussions with the Food and Drug Administration next year about which further experiments they need in order to launch a small pilot trial to transplant genetically modified pig kidneys into people.

Dr. Tector says any pilot trial would likely involve people over the age of 65, one of the fastest-growing groups on the kidney-transplant waiting list of the United Network for Organ Sharing. Patients who are older are particularly vulnerable to dying before getting a transplant because of very long waiting times.

“For some, this will be their only option to get a kidney,” says Dr. Tector.
Luhan Yang, president, chief scientific officer and co-founder of EGenesis Bio, which is focused on making genetically modified pigs whose organs can be used for transplants in humans. PHOTO: DHEERA VENKATRAMAN

Bernhard Hering, director of the University of Minnesota islet cell transplant program, and Christopher Burlak, scientific program director of the university’s Schulze Diabetes Institute, are using Crispr to study genetically modified pig pancreatic islets, which are clusters of cells, some of which produce insulin.

The goal is to create pig islets that the human immune system won’t recognize as foreign, so they can be transplanted into people with Type 1 diabetes without the patients’ having to take immunosuppressive drugs to prevent rejection.

The scientists say they want to gather more data before trying the modified pig islets in people. “What will happen if we cause a major complication?” says Dr. Hering. “We want our first patient to benefit.”

In light of advances such as Crispr, the International Xenotransplantation Association updated its consensus statement this year, saying that in preclinical work, five of eight animals that get the modified porcine islets need to survive six months or longer. Dr. Burlak said that the surviving animals should be healthy and diabetes-free.

A spokeswoman for the FDA said in an email that applications to start human studies will be evaluated on a case-by-case basis, with viruses being a key concern. Some pig viruses may be new and not picked up by current techniques or be latent and cause disease years later. She said the FDA recommends that xenotransplantation be limited to people with serious or life-threatening diseases for whom other therapies aren’t available or aren’t adequate.

Write to Amy Dockser Marcus at amy.marcus@wsj.com

http://www.wsj.com/articles/potent-fix-for-transplant-shortage-genetically-modified-pigs-1480604400