R01 Grant: Understanding and Treating the Mechanisms Behind Biliary Atresia

Biliary atresia is a rare disease, but its impact on children can’t be overstated. The condition is the leading indication for pediatric liver transplant, and it comes with many complications that present daily challenges for the kids and families facing it.

For kids with biliary atresia, onset occurs before birth and comes with progressive obstruction of the extrahepatic bile ducts — the structures that drain bile from the liver into the intestine. This causes liver injury that progresses rapidly into the need for liver transplant. Through a new National Institutes of Health R01 grant, Sarah Taylor, MD, pediatric gastroenterologist and transplant hepatologist at Children’s Hospital Colorado, is prioritizing pathways and treatments that may delay transplant in kids with biliary atresia.

Currently, there is just one procedure that can slow disease progression. Even with this surgical intervention, known as the Kasai portoenterostomy procedure, about 50% of patients need a transplant before they reach 2 years old.

“Ideally, we want to avoid transplant in infancy,” Dr. Taylor says. “And usually, the patients that progress so rapidly to transplant end up being very, very sick. The sicker you go into the transplant, the more complications you may have afterwards. I’m trying to prolong transplant-free survival as my overall goal.”

Investigating new treatment targets

Dr. Taylor and her research team were awarded this grant for their work related to the immune mechanisms behind cholestatic liver disease, and particularly biliary atresia. The team is focusing specifically on metabolites called polyamines. These metabolites regulate macrophage function, which is responsible for clearing out the dead cells and debris that may cause inflammation across the body.

“When you have liver injury in biliary atresia, you have accumulation of dead or apoptotic cells,” Dr. Taylor explains. “They stimulate excess inflammation, which can ultimately lead to scarring and fibrosis.”

In preliminary research, the team found that higher levels of polyamines at diagnosis were associated with improved outcomes for patients. Dr. Taylor says she suspects these metabolites can have a beneficial effect for patients with biliary atresia and plans to dive deeper into which macrophages are most impacted by these polyamines.

“I think where this work will directly take us is more functional studies that show us how we can manipulate macrophage function as a therapeutic target,” Dr. Taylor says.

While she doesn’t expect this work to be curative, Dr. Taylor sees great potential in how the outcomes of this research might help delay transplant in kids with biliary atresia to improve outcomes and recovery.