First in a two-part series on metabolic liver disease. Read part 2.
In the clinical world, Boston Children’s Hospital surgeon Khashayar Vakili, MD, specializes in liver, kidney and intestinal transplant surgeries, while in the lab he is doing work which, for some patients, could eliminate the need for a transplant surgeon altogether.
Vakili has been working at Boston Children’s for six years. During his transplant surgery fellowship, he spent several months learning about pediatric liver transplantation from Heung Bae Kim, MD, director of the Boston Children’s Pediatric Transplant Center, which prompted his interest in the field.
“When the opportunity to join the transplant team presented itself, I did not hesitate to accept,” he says.
Avoiding liver transplant for patients with metabolic disorders
One of Vakili’s most promising research projects involves autologous hepatocyte transplantation—transplanting not the liver but only the liver cells, and doing so using cells from the patient to avoid the need for immunosuppression. Along with Fernando Camargo, PhD, of the Stem Cell Program at Boston Children’s Hospital, Vakili is looking for ways to correct the enzyme defect in patients with metabolic disorders, who make up 13 percent of pediatric liver transplants across the nation. Although the project is in its early stages, Vakili believes the potential implications are promising.
Inherited metabolic disorders occur as the result of an enzyme deficiency. The loss of the enzyme can cause an increase in waste products such as ammonia, which can build up in the blood and be toxic to the brain and liver. If children are no longer able to be managed medically and through diet, transplantation becomes a necessity.
Once the liver is transplanted, the missing enzyme is introduced and the child no longer needs to be on a special diet; there is no longer a risk of neurological side effects. But this also means the child must undergo major surgery and take daily immune-suppressing medications.
Cell transplants, on their own, do not eliminate the need for these medications. “The problem with hepatocyte transplantation is that these cells still come from donor livers, and the body still wants to reject them,” Vakili says. “It works transiently for a few months and then the effects go away, and it still requires immunosuppression. So you can bypass the surgery, but in a few months the child would need another donor.”
Testing the theory
Vakili and Carmargo wanted to find out if a patient’s own hepatocytes could be corrected and transplanted back into the liver. “If we can correct the cells, expand them and give them back to the patient, we can remove the risk of rejection,” says Vakili. “I gave Fernando cells from a patient, and he’s been working on isolating the stem cells from the liver and correcting the genetic mutation.”
Over the past few months, they have been able to correct the gene and expand those cells in a petri dish, but now they must wait to see how the cells will function once they have been transplanted in mice.
“Once you fix the gene cells in a dish, you have to make sure these cells will actually become liver cells in the right environment,” Vakili explains.
If the mouse study is a success, it raises the possibility of bypassing both transplant and immunosuppression. But it is not without risk: as with any genetic modification, there is always an increased risk of cancer. But with better molecular technology over time, Vakili says, the risks of genetic modification might become less than the risks of transplantation. “The fact they were able to correct the gene is promising. I am looking forward to seeing what happens to the mice and seeing if these cells will become liver cells. Hopefully, in the next few months we will see just how promising this is.”
Battling liver tumors
In a separate line of research, Vakili is looking for a mechanism to decrease the growth of hepatocellular carcinoma, the most common primary cancer of the liver. Transplant and surgery alone are usually ineffective for hepatocellular carcinoma because of the aggressive nature of the disease and the fact that there is no chemotherapy that actually works against the tumor.
“Once a liver cell becomes a tumor cell it doesn’t do the normal things a liver cell does,” says Vakili. “All it wants to do is divide and invade blood vessels and go elsewhere. So we look at the tumor cell signaling patterns and try to figure out how the machinery of the cell is different from normal, which cells we need to target to slow things down, and at what point we can interfere to stop its growth.”
Vakili’s study of liver tumors is important to him because on a number of occasions he has seen children present with liver tumors undergo advanced surgical resection or transplantation, but due to the biology of the tumor, it recurs. By studying individual patient tumors, he hopes to gain a greater understanding of the tumor’s biology with the goal of finding new therapeutic targets.