User login
The long-struggling field of cardiac xenotransplantation has had a very good year.
In January, the University of Maryland made history by keeping a 57-year-old man deemed too sick for a human heart transplant alive for 2 months with a genetically engineered pig heart. On July 12, New York University surgeons reported that heart function was “completely normal with excellent contractility” in two brain-dead patients with pig hearts beating in their chests for 72 hours.
The NYU team approached the project with a decedent model in mind and, after discussions with their IRB equivalent, settled on a 72-hour window because that’s the time they typically keep people ventilated when trying to place their organs, explained Robert A. Montgomery, MD, DPhil, director of the NYU Langone Transplant Institute.
“There’s no real ethical argument for that,” he said in an interview. The consideration is what the family is willing to do when trying to balance doing “something very altruistic and good versus having closure.”
Some families have religious beliefs that burial or interment has to occur very rapidly, whereas others, including one of the family donors, were willing to have the research go on much longer, Dr. Montgomery said. Indeed, the next protocol is being written to consider maintaining the bodies for 2-4 weeks.
“People do vary and you have to kind of accommodate that variation,” he said. “For some people, this isn’t going to be what they’re going to want and that’s why you have to go through the consent process.”
Informed authorization
Arthur L. Caplan, PhD, director of medical ethics at the NYU Langone Medical Center, said the Uniform Anatomical Gift Act recognizes an individual’s right to be an organ donor for transplant and research, but it “mentions nothing about maintaining you in a dead state artificially for research purposes.”
“It’s a major shift in what people are thinking about doing when they die or their relatives die,” he said.
Because organ donation is controlled at the state, not federal, level, the possibility of donating organs for xenotransplantation, like medical aid in dying, will vary between states, observed Dr. Caplan. The best way to ensure that patients whose organs are found to be unsuitable for transplantation have the option is to change state laws.
He noted that cases are already springing up where people are requesting postmortem sperm or egg donations without direct consents from the person who died. “So we have this new area opening up of handling the use of the dead body and we need to bring the law into sync with the possibilities that are out there.”
In terms of informed authorization (informed consent is reserved for the living), Dr. Caplan said there should be written evidence the person wanted to be a donor and, while not required by law, all survivors should give their permission and understand what’s going to be done in terms of the experiment, such as the use of animal parts, when the body will be returned, and the possibility of zoonotic viral infection.
“They have to fully accept that the person is dead and we’re just maintaining them artificially,” he said. “There’s no maintaining anyone who’s alive. That’s a source of a lot of confusion.”
Special committees also need to be appointed with voices from people in organ procurement, law, theology, and patient groups to monitor practice to ensure people who have given permission understood the process, that families have their questions answered independent of the research team, and that clear limits are set on how long experiments will last.
As to what those limits should be: “I think in terms of a week or 2,” Dr. Caplan said. “Obviously we could maintain bodies longer and people have. But I think, culturally in our society, going much past that starts to perhaps stress emotionally, psychologically, family and friends about getting closure.”
“I’m not as comfortable when people say things like, ‘How about 2 months?’ ” he said. “That’s a long time to sort of accept the fact that somebody has died but you can’t complete all the things that go along with the death.”
Dr. Caplan is also uncomfortable with the use of one-off emergency authorizations, as used for Maryland resident David Bennett Sr., who was rejected for standard heart transplantation and required mechanical circulatory support to stay alive.
“It’s too premature, I believe, even to try and rescue someone,” he said. “We need to learn more from the deceased models.”
A better model
Dr. Montgomery noted that primates are very imperfect models for predicting what’s going to happen in humans, and that in order to do xenotransplantation in living humans, there are only two pathways – the one-off emergency authorization or a clinical phase 1 trial.
The decedent model, he said, “will make human trials safer because it’s an intermediate step. You don’t have a living human’s life on the line when you’re trying to do iterative changes and improve the procedure.”
The team, for example, omitted a perfusion pump that was used in the Maryland case and would likely have made its way into phase 1 trials based on baboon data that suggested it was important to have the heart on the pump for hours before it was transplanted, he said. “We didn’t do any of that. We just did it like we would do a regular heart transplant and it started right up, immediately, and started to work.”
The researchers did not release details on the immunosuppression regimen, but noted that, unlike Maryland, they also did not use the experimental anti-CD40 antibody to tamp down the recipients’ immune system.
Although Mr. Bennett’s autopsy did not show any conventional sign of graft rejection, the transplanted pig heart was infected with porcine cytomegalovirus (PCMV) and Mr. Bennett showed traces of DNA from PCMV in his circulation.
Nailing down safety
Dr. Montgomery said he wouldn’t rule out xenotransplantation in a living human, but that the safety issues need to be nailed down. “I think that the tests used on the pig that was the donor for the Bennett case were not sensitive enough for latent virus, and that’s how it slipped through. So there was a bit of going back to the drawing board, really looking at each of the tests, and being sure we had the sensitivity to pick up a latent virus.”
He noted that United Therapeutics, which funded the research and provided the engineered pigs through its subsidiary Revivicor, has created and validated a more sensitive polymerase chain reaction test that covers some 35 different pathogens, microbes, and parasites. NYU has also developed its own platform to repeat the testing and for monitoring after the transplant. “The ones that we’re currently using would have picked up the virus.”
Stuart Russell, MD, a professor of medicine who specializes in advanced HF at Duke University, Durham, N.C., said “the biggest thing from my perspective is those two amazing families that were willing let this happen. ... If 20 years from now, this is what we’re doing, it’s related to these families being this generous at a really tough time in their lives.”
Dr. Russell said he awaits publication of the data on what the pathology of the heart looks like, but that the experiments “help to give us a lot of reassurance that we don’t need to worry about hyperacute rejection,” which by definition is going to happen in the first 24-48 hours.
That said, longer-term data is essential to potential safety issues. Notably, among the 10 genetic modifications made to the pigs, four were porcine gene knockouts, including a growth hormone receptor knockout to prevent abnormal organ growth inside the recipient’s chest. As a result, the organs seem to be small for the age of the pig and just don’t grow that well, admitted Dr. Montgomery, who said they are currently analyzing this with echocardiography.
Dr. Russell said this may create a sizing issue, but also “if you have a heart that’s more stressed in the pig, from the point of being a donor, maybe it’s not as good a heart as if it was growing normally. But that kind of stuff, I think, is going to take more than two cases and longer-term data to sort out.”
Sharon Hunt, MD, professor emerita, Stanford (Calif.) University Medical Center, and past president of the International Society for Heart Lung Transplantation, said it’s not the technical aspects, but the biology of xenotransplantation that’s really daunting.
“It’s not the physical act of doing it, like they needed a bigger heart or a smaller heart. Those are technical problems but they’ll manage them,” she said. “The big problem is biological – and the bottom line is we don’t really know. We may have overcome hyperacute rejection, which is great, but the rest remains to be seen.”
Dr. Hunt, who worked with heart transplantation pioneer Norman Shumway, MD, and spent decades caring for patients after transplantation, said most families will consent to 24 or 48 hours or even a week of experimentation on a brain-dead loved one, but what the transplant community wants to know is whether this is workable for many months.
“So the fact that the xenotransplant works for 72 hours, yeah, that’s groovy. But, you know, the answer is kind of ‘so what,’ ” she said. “I’d like to see this go for months, like they were trying to do in the human in Maryland.”
For phase 1 trials, even longer-term survival with or without rejection or with rejection that’s treatable is needed, Dr. Hunt suggested.
“We haven’t seen that yet. The Maryland people were very valiant but they lost the cause,” she said. “There’s just so much more to do before we have a viable model to start anything like a phase 1 trial. I’d love it if that happens in my lifetime, but I’m not sure it’s going to.”
Dr. Russell and Dr. Hunt reported no relevant financial relationships. Dr. Caplan reported serving as a director, officer, partner, employee, advisor, consultant, or trustee for Johnson & Johnson’s Panel for Compassionate Drug Use (unpaid position) and is a contributing author and adviser for Medscape.
A version of this article first appeared on Medscape.com.
The long-struggling field of cardiac xenotransplantation has had a very good year.
In January, the University of Maryland made history by keeping a 57-year-old man deemed too sick for a human heart transplant alive for 2 months with a genetically engineered pig heart. On July 12, New York University surgeons reported that heart function was “completely normal with excellent contractility” in two brain-dead patients with pig hearts beating in their chests for 72 hours.
The NYU team approached the project with a decedent model in mind and, after discussions with their IRB equivalent, settled on a 72-hour window because that’s the time they typically keep people ventilated when trying to place their organs, explained Robert A. Montgomery, MD, DPhil, director of the NYU Langone Transplant Institute.
“There’s no real ethical argument for that,” he said in an interview. The consideration is what the family is willing to do when trying to balance doing “something very altruistic and good versus having closure.”
Some families have religious beliefs that burial or interment has to occur very rapidly, whereas others, including one of the family donors, were willing to have the research go on much longer, Dr. Montgomery said. Indeed, the next protocol is being written to consider maintaining the bodies for 2-4 weeks.
“People do vary and you have to kind of accommodate that variation,” he said. “For some people, this isn’t going to be what they’re going to want and that’s why you have to go through the consent process.”
Informed authorization
Arthur L. Caplan, PhD, director of medical ethics at the NYU Langone Medical Center, said the Uniform Anatomical Gift Act recognizes an individual’s right to be an organ donor for transplant and research, but it “mentions nothing about maintaining you in a dead state artificially for research purposes.”
“It’s a major shift in what people are thinking about doing when they die or their relatives die,” he said.
Because organ donation is controlled at the state, not federal, level, the possibility of donating organs for xenotransplantation, like medical aid in dying, will vary between states, observed Dr. Caplan. The best way to ensure that patients whose organs are found to be unsuitable for transplantation have the option is to change state laws.
He noted that cases are already springing up where people are requesting postmortem sperm or egg donations without direct consents from the person who died. “So we have this new area opening up of handling the use of the dead body and we need to bring the law into sync with the possibilities that are out there.”
In terms of informed authorization (informed consent is reserved for the living), Dr. Caplan said there should be written evidence the person wanted to be a donor and, while not required by law, all survivors should give their permission and understand what’s going to be done in terms of the experiment, such as the use of animal parts, when the body will be returned, and the possibility of zoonotic viral infection.
“They have to fully accept that the person is dead and we’re just maintaining them artificially,” he said. “There’s no maintaining anyone who’s alive. That’s a source of a lot of confusion.”
Special committees also need to be appointed with voices from people in organ procurement, law, theology, and patient groups to monitor practice to ensure people who have given permission understood the process, that families have their questions answered independent of the research team, and that clear limits are set on how long experiments will last.
As to what those limits should be: “I think in terms of a week or 2,” Dr. Caplan said. “Obviously we could maintain bodies longer and people have. But I think, culturally in our society, going much past that starts to perhaps stress emotionally, psychologically, family and friends about getting closure.”
“I’m not as comfortable when people say things like, ‘How about 2 months?’ ” he said. “That’s a long time to sort of accept the fact that somebody has died but you can’t complete all the things that go along with the death.”
Dr. Caplan is also uncomfortable with the use of one-off emergency authorizations, as used for Maryland resident David Bennett Sr., who was rejected for standard heart transplantation and required mechanical circulatory support to stay alive.
“It’s too premature, I believe, even to try and rescue someone,” he said. “We need to learn more from the deceased models.”
A better model
Dr. Montgomery noted that primates are very imperfect models for predicting what’s going to happen in humans, and that in order to do xenotransplantation in living humans, there are only two pathways – the one-off emergency authorization or a clinical phase 1 trial.
The decedent model, he said, “will make human trials safer because it’s an intermediate step. You don’t have a living human’s life on the line when you’re trying to do iterative changes and improve the procedure.”
The team, for example, omitted a perfusion pump that was used in the Maryland case and would likely have made its way into phase 1 trials based on baboon data that suggested it was important to have the heart on the pump for hours before it was transplanted, he said. “We didn’t do any of that. We just did it like we would do a regular heart transplant and it started right up, immediately, and started to work.”
The researchers did not release details on the immunosuppression regimen, but noted that, unlike Maryland, they also did not use the experimental anti-CD40 antibody to tamp down the recipients’ immune system.
Although Mr. Bennett’s autopsy did not show any conventional sign of graft rejection, the transplanted pig heart was infected with porcine cytomegalovirus (PCMV) and Mr. Bennett showed traces of DNA from PCMV in his circulation.
Nailing down safety
Dr. Montgomery said he wouldn’t rule out xenotransplantation in a living human, but that the safety issues need to be nailed down. “I think that the tests used on the pig that was the donor for the Bennett case were not sensitive enough for latent virus, and that’s how it slipped through. So there was a bit of going back to the drawing board, really looking at each of the tests, and being sure we had the sensitivity to pick up a latent virus.”
He noted that United Therapeutics, which funded the research and provided the engineered pigs through its subsidiary Revivicor, has created and validated a more sensitive polymerase chain reaction test that covers some 35 different pathogens, microbes, and parasites. NYU has also developed its own platform to repeat the testing and for monitoring after the transplant. “The ones that we’re currently using would have picked up the virus.”
Stuart Russell, MD, a professor of medicine who specializes in advanced HF at Duke University, Durham, N.C., said “the biggest thing from my perspective is those two amazing families that were willing let this happen. ... If 20 years from now, this is what we’re doing, it’s related to these families being this generous at a really tough time in their lives.”
Dr. Russell said he awaits publication of the data on what the pathology of the heart looks like, but that the experiments “help to give us a lot of reassurance that we don’t need to worry about hyperacute rejection,” which by definition is going to happen in the first 24-48 hours.
That said, longer-term data is essential to potential safety issues. Notably, among the 10 genetic modifications made to the pigs, four were porcine gene knockouts, including a growth hormone receptor knockout to prevent abnormal organ growth inside the recipient’s chest. As a result, the organs seem to be small for the age of the pig and just don’t grow that well, admitted Dr. Montgomery, who said they are currently analyzing this with echocardiography.
Dr. Russell said this may create a sizing issue, but also “if you have a heart that’s more stressed in the pig, from the point of being a donor, maybe it’s not as good a heart as if it was growing normally. But that kind of stuff, I think, is going to take more than two cases and longer-term data to sort out.”
Sharon Hunt, MD, professor emerita, Stanford (Calif.) University Medical Center, and past president of the International Society for Heart Lung Transplantation, said it’s not the technical aspects, but the biology of xenotransplantation that’s really daunting.
“It’s not the physical act of doing it, like they needed a bigger heart or a smaller heart. Those are technical problems but they’ll manage them,” she said. “The big problem is biological – and the bottom line is we don’t really know. We may have overcome hyperacute rejection, which is great, but the rest remains to be seen.”
Dr. Hunt, who worked with heart transplantation pioneer Norman Shumway, MD, and spent decades caring for patients after transplantation, said most families will consent to 24 or 48 hours or even a week of experimentation on a brain-dead loved one, but what the transplant community wants to know is whether this is workable for many months.
“So the fact that the xenotransplant works for 72 hours, yeah, that’s groovy. But, you know, the answer is kind of ‘so what,’ ” she said. “I’d like to see this go for months, like they were trying to do in the human in Maryland.”
For phase 1 trials, even longer-term survival with or without rejection or with rejection that’s treatable is needed, Dr. Hunt suggested.
“We haven’t seen that yet. The Maryland people were very valiant but they lost the cause,” she said. “There’s just so much more to do before we have a viable model to start anything like a phase 1 trial. I’d love it if that happens in my lifetime, but I’m not sure it’s going to.”
Dr. Russell and Dr. Hunt reported no relevant financial relationships. Dr. Caplan reported serving as a director, officer, partner, employee, advisor, consultant, or trustee for Johnson & Johnson’s Panel for Compassionate Drug Use (unpaid position) and is a contributing author and adviser for Medscape.
A version of this article first appeared on Medscape.com.
The long-struggling field of cardiac xenotransplantation has had a very good year.
In January, the University of Maryland made history by keeping a 57-year-old man deemed too sick for a human heart transplant alive for 2 months with a genetically engineered pig heart. On July 12, New York University surgeons reported that heart function was “completely normal with excellent contractility” in two brain-dead patients with pig hearts beating in their chests for 72 hours.
The NYU team approached the project with a decedent model in mind and, after discussions with their IRB equivalent, settled on a 72-hour window because that’s the time they typically keep people ventilated when trying to place their organs, explained Robert A. Montgomery, MD, DPhil, director of the NYU Langone Transplant Institute.
“There’s no real ethical argument for that,” he said in an interview. The consideration is what the family is willing to do when trying to balance doing “something very altruistic and good versus having closure.”
Some families have religious beliefs that burial or interment has to occur very rapidly, whereas others, including one of the family donors, were willing to have the research go on much longer, Dr. Montgomery said. Indeed, the next protocol is being written to consider maintaining the bodies for 2-4 weeks.
“People do vary and you have to kind of accommodate that variation,” he said. “For some people, this isn’t going to be what they’re going to want and that’s why you have to go through the consent process.”
Informed authorization
Arthur L. Caplan, PhD, director of medical ethics at the NYU Langone Medical Center, said the Uniform Anatomical Gift Act recognizes an individual’s right to be an organ donor for transplant and research, but it “mentions nothing about maintaining you in a dead state artificially for research purposes.”
“It’s a major shift in what people are thinking about doing when they die or their relatives die,” he said.
Because organ donation is controlled at the state, not federal, level, the possibility of donating organs for xenotransplantation, like medical aid in dying, will vary between states, observed Dr. Caplan. The best way to ensure that patients whose organs are found to be unsuitable for transplantation have the option is to change state laws.
He noted that cases are already springing up where people are requesting postmortem sperm or egg donations without direct consents from the person who died. “So we have this new area opening up of handling the use of the dead body and we need to bring the law into sync with the possibilities that are out there.”
In terms of informed authorization (informed consent is reserved for the living), Dr. Caplan said there should be written evidence the person wanted to be a donor and, while not required by law, all survivors should give their permission and understand what’s going to be done in terms of the experiment, such as the use of animal parts, when the body will be returned, and the possibility of zoonotic viral infection.
“They have to fully accept that the person is dead and we’re just maintaining them artificially,” he said. “There’s no maintaining anyone who’s alive. That’s a source of a lot of confusion.”
Special committees also need to be appointed with voices from people in organ procurement, law, theology, and patient groups to monitor practice to ensure people who have given permission understood the process, that families have their questions answered independent of the research team, and that clear limits are set on how long experiments will last.
As to what those limits should be: “I think in terms of a week or 2,” Dr. Caplan said. “Obviously we could maintain bodies longer and people have. But I think, culturally in our society, going much past that starts to perhaps stress emotionally, psychologically, family and friends about getting closure.”
“I’m not as comfortable when people say things like, ‘How about 2 months?’ ” he said. “That’s a long time to sort of accept the fact that somebody has died but you can’t complete all the things that go along with the death.”
Dr. Caplan is also uncomfortable with the use of one-off emergency authorizations, as used for Maryland resident David Bennett Sr., who was rejected for standard heart transplantation and required mechanical circulatory support to stay alive.
“It’s too premature, I believe, even to try and rescue someone,” he said. “We need to learn more from the deceased models.”
A better model
Dr. Montgomery noted that primates are very imperfect models for predicting what’s going to happen in humans, and that in order to do xenotransplantation in living humans, there are only two pathways – the one-off emergency authorization or a clinical phase 1 trial.
The decedent model, he said, “will make human trials safer because it’s an intermediate step. You don’t have a living human’s life on the line when you’re trying to do iterative changes and improve the procedure.”
The team, for example, omitted a perfusion pump that was used in the Maryland case and would likely have made its way into phase 1 trials based on baboon data that suggested it was important to have the heart on the pump for hours before it was transplanted, he said. “We didn’t do any of that. We just did it like we would do a regular heart transplant and it started right up, immediately, and started to work.”
The researchers did not release details on the immunosuppression regimen, but noted that, unlike Maryland, they also did not use the experimental anti-CD40 antibody to tamp down the recipients’ immune system.
Although Mr. Bennett’s autopsy did not show any conventional sign of graft rejection, the transplanted pig heart was infected with porcine cytomegalovirus (PCMV) and Mr. Bennett showed traces of DNA from PCMV in his circulation.
Nailing down safety
Dr. Montgomery said he wouldn’t rule out xenotransplantation in a living human, but that the safety issues need to be nailed down. “I think that the tests used on the pig that was the donor for the Bennett case were not sensitive enough for latent virus, and that’s how it slipped through. So there was a bit of going back to the drawing board, really looking at each of the tests, and being sure we had the sensitivity to pick up a latent virus.”
He noted that United Therapeutics, which funded the research and provided the engineered pigs through its subsidiary Revivicor, has created and validated a more sensitive polymerase chain reaction test that covers some 35 different pathogens, microbes, and parasites. NYU has also developed its own platform to repeat the testing and for monitoring after the transplant. “The ones that we’re currently using would have picked up the virus.”
Stuart Russell, MD, a professor of medicine who specializes in advanced HF at Duke University, Durham, N.C., said “the biggest thing from my perspective is those two amazing families that were willing let this happen. ... If 20 years from now, this is what we’re doing, it’s related to these families being this generous at a really tough time in their lives.”
Dr. Russell said he awaits publication of the data on what the pathology of the heart looks like, but that the experiments “help to give us a lot of reassurance that we don’t need to worry about hyperacute rejection,” which by definition is going to happen in the first 24-48 hours.
That said, longer-term data is essential to potential safety issues. Notably, among the 10 genetic modifications made to the pigs, four were porcine gene knockouts, including a growth hormone receptor knockout to prevent abnormal organ growth inside the recipient’s chest. As a result, the organs seem to be small for the age of the pig and just don’t grow that well, admitted Dr. Montgomery, who said they are currently analyzing this with echocardiography.
Dr. Russell said this may create a sizing issue, but also “if you have a heart that’s more stressed in the pig, from the point of being a donor, maybe it’s not as good a heart as if it was growing normally. But that kind of stuff, I think, is going to take more than two cases and longer-term data to sort out.”
Sharon Hunt, MD, professor emerita, Stanford (Calif.) University Medical Center, and past president of the International Society for Heart Lung Transplantation, said it’s not the technical aspects, but the biology of xenotransplantation that’s really daunting.
“It’s not the physical act of doing it, like they needed a bigger heart or a smaller heart. Those are technical problems but they’ll manage them,” she said. “The big problem is biological – and the bottom line is we don’t really know. We may have overcome hyperacute rejection, which is great, but the rest remains to be seen.”
Dr. Hunt, who worked with heart transplantation pioneer Norman Shumway, MD, and spent decades caring for patients after transplantation, said most families will consent to 24 or 48 hours or even a week of experimentation on a brain-dead loved one, but what the transplant community wants to know is whether this is workable for many months.
“So the fact that the xenotransplant works for 72 hours, yeah, that’s groovy. But, you know, the answer is kind of ‘so what,’ ” she said. “I’d like to see this go for months, like they were trying to do in the human in Maryland.”
For phase 1 trials, even longer-term survival with or without rejection or with rejection that’s treatable is needed, Dr. Hunt suggested.
“We haven’t seen that yet. The Maryland people were very valiant but they lost the cause,” she said. “There’s just so much more to do before we have a viable model to start anything like a phase 1 trial. I’d love it if that happens in my lifetime, but I’m not sure it’s going to.”
Dr. Russell and Dr. Hunt reported no relevant financial relationships. Dr. Caplan reported serving as a director, officer, partner, employee, advisor, consultant, or trustee for Johnson & Johnson’s Panel for Compassionate Drug Use (unpaid position) and is a contributing author and adviser for Medscape.
A version of this article first appeared on Medscape.com.