杏吧原创

Several groups are vying to be the first to transplant organs from genetically modified pigs into people as part of a clinical trial. One of the contenders is a team in China that last year was the first to complete a human trial of CRISPR genome-edited pig skin grafts.

鈥淲e plan to do heart or liver xenotransplants within 2022, but we do not have a specific timetable at this moment,鈥� Lijin Zou at the First Affiliated Hospital of Nanchang University in China told New 杏吧原创.

鈥淲e are completing all the technical and medical preparations, including the preparation of surgeons and the ICU team for solid organ xenotransplants,鈥� he says. 鈥淐urrently, we are in the middle of seeking all the necessary approvals.鈥�

Teams around the world are genetically modifying pigs to make their organs less likely to be rejected by the immune system after transplantation. Zou鈥檚 team has removed three genes from a strain of miniature pig and added eight human genes.聽The changes are similar to those made to the pig that provided the heart transplanted into David Bennett by surgeons at the University of Maryland School of Medicine on 7 January. That line of pigs was created by US company Revivicor, part of United Therapeutics.

Last year, Zou鈥檚 team carried out a clinical trial involving 16 people with burns. Each person had a 鈥淴eno X鈥� skin graft from the modified pigs placed alongside a material derived from unmodified pigs. No drugs were given to stop their bodies rejecting the grafts.

When people have severe burns, it is often necessary to temporarily cover the wounds with skin from human cadavers or from pigs to prevent infection and the loss of fluid, and to help prepare the site for a skin graft taken from elsewhere on the body.

In recently reported results from the trial, the material from unmodified pigs never linked up with blood vessels in the underlying human tissue to get a blood supply, and lasted just eight days. Skin from human cadavers also typically lasts eight days when used in this way. The skin from the modified pigs quickly developed a blood supply. The grafts did start to be rejected, as expected, but survived for 25 days, after which they were removed. None of the聽people treated had any adverse reactions or developed infections.

鈥淥ur unprecedented work demonstrates that the Xeno X skin could be an effective treatment for severe burns, particularly when human cadaveric skin is in short supply,鈥� says Zou. 鈥淔or broader burn management, xeno skin transplants will be a game changer.鈥�

Other experts say the results are encouraging. 鈥淭he availability of a modified xenograft that lasts longer could be of significant benefit to patients with large and deep wounds,鈥� says at Stony Brook University in New York.

In the US, with began in 2019, but it isn鈥檛 due to be completed until later this year.

Zou says his team will now expand the trial and include people with life-threatening burns. The team is also making further genetic changes to pigs to improve the skin. It might eventually be possible to create pigs whose skin looks and functions just like human skin, and could be a long-term replacement, he says.

The team also hopes to get the go-ahead to transplant organs from the modified pigs into people about to die while awaiting a human organ. Initially at least, the pig organs would be a temporary measure and would be replaced by ones from humans. The team is likely to start with heart transplants.

鈥淏ecause the heart鈥檚 main function is a biological pump, there is less of a physiological barrier between the pig and the human in the heart than other organs,鈥� says Zou.

鈥淭he Chinese project looks promising,鈥� says at the Trauma Hospital Berlin in Germany. But long-term trials need to be done, he says.

Several groups in the US are also waiting on regulatory approval to commence such trials. at the University of Maryland School of Medicine, whose team was allowed to transplant the Revivicor pig heart into Bennett as a last resort rather than as part of a trial, says his team is in the process of getting approval for a clinical trial from the US Food and Drug Administration (FDA).

鈥淗owever, the FDA wants us to do further non-human primate studies before they give us this permission. Mr Bennett鈥檚 survival definitely helps our cause, but the FDA was very clear that his case and further cases like this cannot be used as an alternative for formal clinical trials,鈥� says Mohiuddin.

Animal studies show that hearts from normal-sized pigs can grow too large after transplantation. In the pig line that provided the heart for Bennett, Revivicor has deleted a gene for a growth hormone receptor to try to prevent this.

Zou thinks his team鈥檚 use of miniature pigs will prove to be an advantage in this regard. 鈥淥ur pigs are mini-pigs, with a comparable body weight to humans,鈥� he says.

Last year, two teams temporarily transplanted Revivicor pig kidneys into brain-dead people, and at least one of these teams aims to start clinical trials soon.聽鈥淲e are very hopeful that we would be able to implement a phase I trial later this year,鈥� said at the University of Alabama at Birmingham at a press conference on 20 January. 鈥淲e do have a herd of pigs that would be ready.鈥�

Also in the race is a US company called eGenesis that has, in collaboration with a Chinese company called , created pigs with even more extensive changes than those modified by Zou鈥檚 team and Revivicor.

鈥淲e are meeting with the FDA in the middle of this year for both our kidney and [insulin-producing] islet cell programmes,鈥� says a spokesperson for eGenesis. 鈥淲ith their guidance, we will move our programmes into the clinic as quickly as possible.鈥�

Qihan Biotech and another US xenotransplant company called Makana Therapeutics, part of bioengineering firm Recombinetics, didn鈥檛 respond to questions about their plans for clinical trials.

A team at Ludwig Maximilian University in Germany is also modifying pigs for transplantation, but the animals .

One of the many benefits of a plentiful supply of cheap organs from modified pigs is that it should reduce unethical practices related to procuring human organs for transplants.聽In particular, the sources of human organs in China remain controversial. Most used to come from executed prisoners. China says this practice stopped in 2015. However, there is evidence that organs are being taken from prisoners without consent.

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