About a year ago, scientists grafted genetically modified pigs’ hearts into baboons. And now, the team reports that the baboons and their pig hearts are doing just fine. The engineering grafts haven’t been rejected, and ones like it may be ready for humans with end stage heart failure one day soon.
The biggest challenge with transplants using animal organs (or xenotransplantation) is preventing the hosts from seeing their donor parts as foreign. In the past, organs that haven’t been genetically tweaked last no more than six months in primates before they’re rejected. One of the reasons pigs were chosen for this study is because their anatomy is already compatible with humans; pig valves are already being swapped for human heart valves.
To further help pig parts evade our immune systems, a team from the National Heart, Lung, and Blood Institute (NHLBI) of the U.S. National Institutes of Health added several human genes to the pig genome -- while removing (or knocking out) genes that would trigger immune responses in humans.
The modified pig hearts were then transplanted into the abdomen of baboons alongside their own hearts. The baboons were treated with drugs that suppress their immune systems. So far, the combination of donor genetic modifications and host-targeted immunosuppression seems to work: Four xenografts have survived in the baboons for over a year. This is already twice as long as previously reported. The next step is to actually replace the original baboon heart with pig hearts to see if they can provide full life support.
In case you want to know the specifics about the genetic modifications made in the 4- to 6-week-old piglets: They are alpha galactosidase transferase knockout (GTKO) pigs expressing the human complement regulatory gene CD46 (hCD46) and the Thrombomodulin (hTM) molecule. As for the immunosuppression: The baboons were receiving drugs that suppressed both T and B immune cells, as well as anti CD40 and CD154 antibody and conventional non-specific immunosuppressive agents.
Both of the control (unmodified) xenographs were rejected within one day of transplantation. The eight GTKO grafts expressing human CD46 molecules and receiving the anti CD 154 antibody survived an average of 70 days, with the longest survival of 236 days. The anti CD40 treated baboons with immunosuppression survived for an average of 84 days. The four grafts from the GTKO-hCD46-hTM pigs along with a higher dose of anti CD40 have the longest graft survival: still surviving as they approach the one-year mark (as of the abstract submission date). It's been over 500 days now.
The team believes that using animal parts may solve the shortage of organ donors. In the U.S., for example, approximately 3,000 people are on mechanical assist devices waiting for a heart transplant -- about 2,000 donor hearts become available year.
"We are hopeful that we will be able to repeat our results in the life-supporting model,” NHLBI’s Muhammad Mohiuddin says in a news release. “If successful, this method could change the current transplant paradigm, eliminating the shortage of donor organs including hearts, livers, kidneys, intestine, as well as insulin producing cells for treatment of diabetes.” The technique also means that fewer potentially toxic immunosuppressive drugs will be needed. Researchers will only move on to human trials if it works in baboons.
But aside from concerns over GE animal parts, the technique could one day be surpassed by regenerative medicine using stem cells, tissue engineering, and lab-grown parts. However, “I think we are a long way off from being able to genetically engineer a whole heart though stem cells so this could provide a good stop-gap,” Chris Mason of University College London tells the Telegraph.
The latest findings were presented at the 94th American Association for Thoracic Surgery meeting this week in Toronto. The work was first published in the American Journal of Transplantation last year.
Image: History of Medicine / NIH