Xenotransplants: not quite around the corner

Pig hearts, kidneys and livers could be available for transplant into humans within five to seven years, according to the latest reports from the American Association for the Advancement of Science meeting currently underway in Boston.

Two companies, PPL Therapeutics and Immerge BioTherapeutics, have created cloned pigs that lack the gene that triggers organ transplant rejection in monkeys.

But the biotech company that is likely to reap at least some of the rewards from such breakthrough is an Australian one - BresaGen.

"Although we may not have been first to clone the 'knockout' pigs, we will receive royalties," said Prof Tony D'Apice, BresaGen collaborator and director of xenotransplant projects at St Vincent's Hospital, Melbourne.

In Australia, BresaGen's patent has been issued and in the US and Europe it is pending. "The patent covers an animal without the alpha 1,3 gal gene" D'Apice said. "We have patented the mouse model and have filed a patent to extend to pig species."

Since 1992, BresaGen has been doing porcine xenotransplants in baboons and artificial systems.

"This is the problem we face: if we do a transplant, it is rejected, but by removing this gene we hope to overcome the hyper-acute rejection that happens in the first 15 minutes" D'Apice said. "It's a significant step, but it's not the final modification because there are other rejections steps that follow."

Two US companies have cloned piglets with one copy of the gene knocked out. "They need to knock out both copies," D'Apice said. BresaGen was first to 'knock out' both copies of the GGTA1 gene in mice back in 1996. Now the company is using cloning technology and gene targeting technologies to knock out both copies of the porcine GGTA1 gene. "Whether other companies will need to license our IP, in the end, will be up to the lawyers to sort out," D'Apice said.

The GGTA1 enzyme is responsible for manufacturing a cell surface carbohydrate that, if present on the cells of a pig organ or tissue transplanted into a human, would be recognised as foreign by the recipient's immune system and trigger rapid organ rejection. "From principal research we know that a transplanted heart organ undergoes hyper-acute rejection if it contains one copy of the alpha 1,3 gal gene," D'Apice said.

Cloning piglets without the gal is a multi-step process. The first step is knocking out one copy of the gal gene and next step is knocking out the second copy of the gene. There are two approaches; retrieving fibroblasts from the knockout pigs and retargeting the second gene; or cross-breeding the knockout pigs and selecting the next GGTA1-free generation. "Cross-breeding can take up to two years but re-targeting will take as little as six months," D'Apice said.

No matter which approach is used, there are major hurdles ahead. "We still have to prove the homozygous GGTA1 gene knockout is viable" D'Apice said. "We've made an important step in the process but people should not be too excited about the prospect of xenotransplants tomorrow morning."