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Mechanistic Processes That Drive Rare Progressive Familial Intrahepatic Cholestasis Type 1

June 14, 2022

UPMC Children’s Hospital of Pittsburgh Division of Pediatric Gastroenterology, Hepatology and Nutrition faculty member James E. Squires, MD, MS, was awarded a new pilot and feasibility grant from the Childhood Liver Disease Research and Education Network (ChilDReN) to study the mechanistic processes underlying the development of the rare genetic liver disorder known as progressive familial intrahepatic cholestasis type 1 (PFIC1). 

Dr. Squires is an associate professor of Pediatrics and is the co-director of the Hepatology Program at UPMC Children's and director of the Pediatric Transplant Hepatology Fellowship Program.

Collaborating with Dr. Squires on the study are co-investigator Alejandro Soto-Gutierrez, MD, PhD, associate professor in the Department of Pathology at the University of Pittsburgh School of Medicine, and Rodrigo Machado-Florentino, PhD, a postdoctoral associate in the Department of Pathology and a researcher at the Pittsburgh Liver Research Center.

About PFIC1

Progressive familial intrahepatic cholestasis comprises a cluster of rare disease variants that are driven by genetic mutations in six genes that have been found to date, with additional genes under investigation. Each of the identified genes codes for specific mutant proteins that are responsible for the underlying phenotypes of PFIC. These protein mutations lead to abnormal bile production and transport in hepatocytes that produce numerous complications in patients, such as fibrosis, portal hypertension, pruritus, and chronic liver disease or liver failure.

PFIC1 was first identified in 1969 in a cluster of Amish patients in western Pennsylvania. It wasn’t until 1998 that the underlying mutated gene was identified – the ATP8B1 gene – and its abnormally coded protein, FIC1.

Since that time, little has been understood about the FIC1 protein's mechanistic processes, specifically how the protein functions to drive the PFIC1 subtype of the disease.

"Progress in understanding the nature of this disease has been plodding," says Dr. Squires. "This is because of how exceptionally rare the disorder is and how difficult it has been to study the basic science aspects of the FIC1 protein in animal models. Mouse and other models are just not that good at recapitulating what is happening in the human liver. However, our team has a new approach to get past this roadblock."

Study Overview and Goals

Dr. Squires and colleague’s pilot study build upon previous work they established in the laboratory that can take skin cell biopsies from patients with PFIC and modify those cell lines to become pluripotent stem cells from which they can then generate lines of human hepatocytes in which to study how the FIC1 protein functions.

"The skin biopsy approach and transformation of those cells into pluripotent stem cells and ultimately hepatocyte lines allow us to create human-centric models for our study in a relatively non-invasive manner. The underlying mutation in ATP8B1 and the mutated FIC1 protein are carried forward so we can study their abnormal function and the processes which they influence in human cells," says Dr. Squires.

Dr. Squires and the team will build upon the existing cell lines they have created with additional PFIC patient specimens in order to further their studies of the mechanistic processes at play. They will employ gene-editing techniques using CRISPR/Cas9 tools to modify and probe the molecular actions of the FIC1 protein.

If successful, their cellular models for PFIC1 could then be applied to other PFIC variants or other types of cholestatic diseases

"We must understand the basic processes at play with the FIC1 protein to move forward any possible therapeutic targets for potential development," says Dr. Squires. "Because of how rare the disorder is and the past difficulties with studying it, we are really at the beginning of the journey with this research, but we are hopeful that our approach will begin to crack open the mysteries of how this protein functions to disrupt cholestatic functions leading to a debilitating and incurable liver disease."

Learn more about Dr. Squires, Dr. Soto-Gutierrez, Dr. Machado-Florentino, the Pittsburgh Liver Research Center, and the ChiLDReN Network.