2024 Conference Agenda - PFIC

We’ve got an incredible lineup of talks and presentations from PFIC experts this year!

Read on for detailed sessions descriptions, information about our presenters and to view the abstracts from the poster session!

Click to jump to a specific section to view details for each of the sessions:

Family Sessions

Research Workshop Sessions

Family-Researcher Roundtables

Poster Session Abstracts

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Family Sessions

Session topics and descriptions for the Family Sessions were created based on information gathered from the patient and parent community, highlighting what they want to learn more about. Information was gathered during focus groups, surveys and polling, and general discussion in community support groups. For each talk, the presenter with a community member who reviewed their talk to make sure it was understandable by a lay audience.

Current and Emerging Treatment Landscape

This topic will explore the latest evidence related to current treatments and surgical interventions that are most effective in (1) reducing itch related to PFIC and (2) delaying liver transplant. Is there evidence that shows variability per PFIC subtype? Current treatments include antipruritics, bile acid and non-bile acid modulators, other (off-label) treatments, surgical diversions. Additionally, this session will review the latest research on the newest treatment landscape, the IBAT inhibitors.

Learnings from this session will complement roundtable discussions, when families and researchers will discuss patient experiences with current management pathways. Treatments that are still in clinical trial or pre-clinical phase will be discussed in the later session, the Future Treatments of PFIC.

Watch a recording in our Webinar Library!

Speaker: Dr. Paula Hertel

Click To Read Speaker Bio

https://www.texaschildrens.org/find-a-provider/paula-marie-hertel-md

Dr. Hertel is a pediatric gastroenterologist and hepatologist at Texas Children’s Hospital and Associate Professor of Pediatrics at Baylor College of Medicine in Houston, Texas. Her career is dedicated to caring for children with liver disease and liver transplant, and to clinical research in pediatric liver disease. She has a particular passion for the care of children with cholestatic liver diseases, including PFIC, and to the study of these complex disorders. She is a member of the PFIC Writing Group for the National Institutes of Health (NIH) “ChiLDReN” liver research network, and helped to lead this group’s effort in a baseline analysis of children diagnosed with PFIC enrolled in the Network. At this time, she is working with the PFIC Writing Group on a follow-up study that will include an analysis of serum specimens to determine if lysophosphatidylcholine (LPC) can serve as an effective biomarker (blood test) for itch in children with PFIC. This work is supported by a PFIC Network Small Research Grant , for which she was a recipient.

Dr. Hertel is also the Texas Children’s Hospital site’s Principal Investigator for the NIH-sponsored NASH Clinical Research Network, which is focused on study of children and adults with MASLD and MASH (fatty liver disease), and is an ongoing contributor to work published by this group. She lives in Houston with her husband, two children, pet dog and parrot, and enjoys reading and travel in her free time. She is extremely grateful to the families and donors of the PFIC Network and thoroughly enjoys the opportunity to participate in the Network’s unique and important collaboration between physicians, researchers, and families.

PFIC in Adults: Diagnosis & Onset

PFIC has historically been diagnosed in pediatrics, however in recent years increasing knowledge has led to the diagnosis of PFIC and related diseases in teens and adults. Within the past 5 years, an increasing number of publications are highlighting the spectrum of disease, and adult hepatologists will need to become increasingly aware of these diseases both for diagnosis and adequate management.

Watch a recording in our Webinar Library!

Speaker: Dr. Silvia Vilarinho

Click To Read Speaker Bio

https://www.vilarinholab.org/
https://medicine.yale.edu/internal-medicine/digestivediseases/profile/silvia-vilarinho/

Silvia Vilarinho is a physician-scientist who uses genetics, genomics and human samples to investigate the molecular basis of various liver diseases of unknown etiology. Using these approaches, we have identified five novel genetic liver diseases. Our research goal is to continue to discover new genes important in liver function both in health and disease and to use cell biology and animal models to determine the specific mechanism(s) linking mutant gene to disease as a roadmap to further understand and treat rare and common liver diseases. This research approach provides new knowledge with direct impact in improving patient care and creates an outstanding scientific environment to train future physician-scientists and trainees with particular interest in human disease. Furthermore, Dr. Vilarinh is very committed to make ‘genomic medicine for liver disease’ a reality in clinical practice worldwide.

Pre-Transplant Diet & Nutrition- Panel Presentation and Discussion

This session focuses on nutritional management in PFIC in the pre-transplant population. In this unique panel discussion, we will explore the topic from multiple perspectives, including that of a pediatric hepatologist, a registered dietitian, and a PFIC parent. Panel participants will share their experiences and best practices in relation to dietary and vitamin management, considerations for patients who experience diarrhea as a symptom or a side effect, and how access can affect management and care. Panelists will touch briefly on PFIC1-specific considerations post-transplant, but the main focus will be on the population who has not yet experienced transplant.

Watch a recording in our Webinar Library!

Panelists:

Dr. Ronald Sokol Bio

https://som.cuanschutz.edu/Profiles/Faculty/Profile/5796

Ronald J. Sokol, MD, FAASLD, Distinguished Professor of Pediatrics, received his medical degree from the University of Chicago Pritzker School of Medicine and completed pediatric residency training and Chief Residency at the University of Colorado (CU) School of Medicine. He completed fellowship training in Pediatric Gastroenterology and Nutrition at Cincinnati Children’s Hospital Medical Center and the University of Cincinnati. He has been a faculty member at University of Colorado School of Medicine since 1983. He was the founding Director of the Pediatric Liver Center at CU School of Medicine and his clinical interests are congenital, genetic and metabolic liver diseases of infants and children. His research includes basic, translational and clinical studies and trials centered on the pathogenesis, mechanisms, nutrition and treatment of childhood cholestatic liver diseases. He has been Chair of the Steering Committee, Executive Committee and Administrative Core of the multi-site NIDDK/NIH funded Childhood Liver Disease Research Network (ChiLDReN) since its inception in 2002. Currently, he is the Chief Scientific Officer, Child Health at CU Anschutz Medical Center and Children’s Hospital Colorado and Associate Dean for Child Health Research at CU SOM. He has been the Principal Investigator and Director of the Colorado Clinical and Translational Sciences Institute (funded by NCATs CTSA awards) since 2008 and the Assistant Vice Chancellor for Clinical and Translational Science at CU Denver. He was Section Head of Pediatric Gastroenterology, Hepatology, and Nutrition for 16 years until May 2022. He is past President of AASLD and NASPGHAN. He has authored over 300 peer-reviewed papers, 130 book chapters, review articles and books and is co-editor of the leading pediatric liver disease textbook, Liver Disease in Children.

Elizabeth Tamayo Bio

https://som.cuanschutz.edu/Profiles/Faculty/Profile/5796

Elizabeth Tamayo, RD, LD, CNSC, is a registered dietitian with the Nutrition Therapy Department at Cincinnati Children’s Hospital Medical Center (CCHMC). She graduated from The Ohio State University in 2018 with a Bachelor of Science in Medical Dietetics. Elizabeth has been a practicing dietitian at CCHMC for more than five years and has been the liver and small bowel transplant dietitian in both the inpatient and outpatient settings at CCHMC for over four years. She is a Certified Nutrition Support Clinician (CNSC).

Sharon Munn Bio

Sharon is a PFIC mother from Canada.

Moderator:

Dr. Laura Bull Bio

https://profiles.ucsf.edu/laura.bull

Laura Bull, Ph.D., RDN is a Professor in the Liver Center of the Department of Medicine at UCSF (University of California San Francisco). She is also affiliated with the UCSF Institute for Human Genetics. Her research has focused upon understanding the genetic causes and manifestations of pediatric and pregnancy-related cholestasis.

Patient-Centered Outcomes & the PFIC Network Patient Registry

This presentation gives an update on the PFIC Network Patient Registry.
The registry started two years ago: We launched during the PFIC Family & Scientific Conference in 2022, and have about 120 participants!
The registry collects data every 6 months: Multiple waves permit to see how a patient fares over time. For instance, several participants had liver transplant (LT) after they enrolled in the registry, and we can see the effect of LT on itch, sleep, family quality of life, and general health.
The registry collects high quality data: We use validated survey questions and measures so that we can show for instance in which percentile of severity a patient falls with respect to itch or growth retardation.
The registry is patient-focused and patient-driven: When patient families indicated the importance to look at the financial burden associated with PFIC we added several questions to the registry to address this issue.
The registry is an open science project: Researchers can apply for access to de-identified data. All requests are evaluated by a committee of patient families and researchers/clinicians.

Watch a recording in our Webinar Library!

Speaker: Dr. Gitta Lubke

Click To Read Speaker Bio

Dr. Lubke works with the PFIC Network as a Science Advisor to help develop a quality research program, write grant proposals, and maintain a patient registry. She is also Co-Lead of the ongoing Projet IMPACT. The goal of IMPACT is to prepare the PFIC community for patient-centered outcomes research by July 2025. IMPACT is funded through a Patient-Centered Outcomes Research Institute (PCORI) Eugene Washington Engagement Award (EASO-30455).

State of the Art: Current Prognosis and Prospects of Liver Transplant

Liver transplantation has become a standard treatment for many liver diseases. However, large scale pediatric liver transplantation has only started in the 80s of the last century. There have been major developments since then, with changes in the diseases that were reason to transplant and also in the prognosis after transplantation. In this presentation the developments in pediatric liver transplantation with an emphasis on the prognosis that has currently been reached. Additionally, the talk will focus on the latest research on recurrence of PFIC disease as well as special considerations for patients who have PFIC 1.

Watch a recording in our Webinar Library!

Speaker: Dr. Henkjan Verkade

Click To Read Speaker Bio

Pediatric Gastroenterology & Hepatology, Dept. Pediatrics
Beatrix Children’s Hospital /
University Medical Center Groningen
P.O. Box 30.001
9700 RB Groningen
The Netherlands
e-mail: h.j.verkade@umcg.nl

Website: https://www.rug.nl/staff/h.j.verkade/

Henkjan J. Verkade is a pediatric gastro/hepatologist at the Beatrix Children’s Hospital of the University Medical Center Groningen, The Netherlands. He received his PhD degree in Medicine cum laude at the University of Groningen on the thesis entitled “Lipid absorption and metabolism”. Henkjan Verkade was a post-doctoral fellow at the University of Alberta, Edmonton, Canada. In 2005 Verkade was appointed Professor of Pediatrics, pediatric gastroenterology/hepatology, at the University Medical Center Groningen.

Henkjan Verkade combines clinical work in pediatric gastro/hepatology with clinical and fundamental research projects. Verkade’s current research projects involve intestinal lipid absorption and metabolism, the enterohepatic circulation, and pediatric liver disease (familial cholestatic syndromes, biliary atresia, liver transplantation). In 2017 he initiated with Bettina Hansen the global NAPPED registry (NAtural Course and Prognosis of PFIC and Effect of Biliary Diversion) and in 2022 the prospective global TreatFIC database. The NAPPED registry has been helpful to further characterize the natural history of progressive familiar intrahepatic cholestasis syndromes and to identify prognostic parameters for the course of disease and for responsiveness to treatments.

Verkade has authored more than 300 peer-reviewed publications and more than 15 book chapters. Since 2019, he is associate editor of the Journal of Pediatric Gastroenterology and Nutrition.

Future Treatments of PFIC

Current treatments for PFIC can help with symptoms caused by the disease, and can slow the disease progression in some, but they don’t fix the root issue: a mutation in one’s genes that causes PFIC disease. Scientists are exploring a potential future where new treatments are designed to fix this root issue, but those treatments come with new risks. It is also important to understand that not every type of PFIC can be treated in the same way, since each subtype of PFIC is the result of a unique type of genetic mutation.

In this talk, we’ll learn about potential new treatments for PFIC. We’ll learn why they’re different from what we have now, how they might vary among PFIC subtypes, and what risks they may carry. This talk will provide helpful information before our discussion in Roundtable #2, where we will take a deeper dive into the potential risks of future treatments and what participating in that research could look like.

Watch a recording in our Webinar Library!

Speaker: Dr. Akihiro Asai

Click To Read Speaker Bio

https://www.cincinnatichildrens.org/research/divisions/g/gastroenterology/labs/asai

My research focus is to develop an effective treatment for inherited cholestasis syndromes by using innovative disease-modeling platforms. We use patient-specific induced Pluripotent Stem Cells (iPSCs) to recapitulate human liver diseases by a cutting-edge method to generate “a liver in the dish.” We have established technologies to induce hepatic differentiation into iPSCs and achieved the robust hepatocellular function of bile acid synthesis and transport. Notably, we have successfully modeled Progressive Familial Intrahepatic Cholestasis type 2 (BSEP deficiency), a representative genetic cholestatic disorder, within our experimental system. This research has unveiled novel pathophysiological mechanisms in this genetic condition, as detailed in our publication in Stem Cell Reports (2020). Furthermore, we have extended our disease modeling efforts to another prototypic genetic cholestatic disorder, PFIC type 4 (TJP2 deficiency), using similar yet refined methodologies. Our research findings, reported in Journal of Hepatology Reports (2022), reveal that TJP2 deficiency in induced hepatocytes (iHep) disrupts cellular polarity when cultured in a monolayer system. These discoveries provide a solid foundation for our current research proposal. In addition to my basic science research, I actively participate as a co-investigator in four clinical studies at our institution, focusing on treatments for HBV and HCV in children, as well as the management of PFIC and pediatric acute liver failure. Additionally, I serve as a site investigator for the LOGIC study, a longitudinal investigation into the genetic causes of intrahepatic cholestasis, as part of the NIH-funded Childhood Liver Disease Network.

After completing my clinical training to become a pediatric gastroenterologist, I joined Dr. Bezerra’s research laboratory at Cincinnati Children’s Hospital Medical Center (CCHMC) as a research fellow. I advanced bench scientific skills and knowledge under the instruction of Drs. James Wells, Takanori Takebe, Jorge Bezerra, Lee Denson, and Stacey Huppert. I have utilized their expertise to master the skills of stem cell culture to investigate cell-cell interaction during hepatocyte differentiation (Development, 2017). In 2016, after completing a one-year clinical fellowship in advanced pediatric transplant hepatology at CCHMC, I joined the faculty of pediatric gastroenterology, hepatology, and nutrition as a physician-scientist and started my independent research laboratory. With secured funding from pilot initiatives and internal research funding, I established an independent research program composed of experts at CCHMC. I have benefitted from the productive environment of CCHMC to interact and collaborate with colleagues in the clinical and basic science realm to address questions that are timely and utilize cutting-edge technology in stem cell biology (Gastroenterology, 2020).

Lay Summary Report of Research Workshop

This will be a lay-friendly summary of the Research Workshop sessions.

Watch a recording in our Webinar Library!

Speakers:

Dr. Chunyue Yin

Dr. William Balistreri

Click To Read Dr. Yin Bio

https://www.cincinnatichildrens.org/research/divisions/g/gastroenterology/labs/yin

Dr. Chunyue Yin obtained her PhD in Developmental Biology at Vanderbilt University and completed her postdoctoral training at the University of California, San Francisco. She started her independent research program at Cincinnati Children’s in 2012, focusing on the etiology of pediatric intrahepatic cholestasis using animal models. She has ongoing collaboration with a team of clinicians, geneticists, and pathologists to investigate how mutations in the known genes cause cholestasis and to identify novel disease-causing genes.

Click To Read Dr. Balistreri Bio

https://www.cincinnatichildrens.org/bio/b/william-balistreri

I have worked at Cincinnati Children’s Hospital Medical Center for more than forty years to better understand liver diseases, such as viral hepatitis, chronic cholestasis, metabolic liver disease and the outcomes of liver transplant in children. Initially driven by curiosity, I work to find a cure for these types of diseases, so children can live better, more fulfilling lives.
I served as the director of the Division of Pediatric Gastroenterology, Hepatology and Nutrition for 25 years. My research publications (over 580 to date) have helped broaden our understanding of many aspects of liver disease in children.

In 2000, I became the first pediatrician to serve as president of the American Association for the Study of Liver Diseases. I have also received numerous awards and honors, including:
-American Academy of Pediatrics, Murray Davidson Award
-American Association for the Study of Liver Diseases, Distinguished Service Award
-American Gastroenterological Association, Distinguished Educator Award
-Canadian Liver Foundation and the Canadian Association for the Study of Liver, Andrew Sass-Kortsak Memorial Award
-Cincinnati Pediatric Society, Founder’s Award
-Crohn’s and Colitis Foundation of America, Distinguished Leadership Award
-Ohio Chapter of the American Academy of Pediatrics, Outstanding Pediatrician Award
-North American Society for Pediatric Gastroenterology, Hepatology and Nutrition Shwachman Award
-University of Buffalo, Distinguished Alumnus Award
-University of Cincinnati, College of Medicine Daniel Drake Medal

I have also been listed among the Best Doctors in America numerous times in a variety of publications. I thank all the volunteers who continue to help us better understand liver disease.

Jump to:

Research Workshop

Family-Researcher Roundtables

Poster Abstracts

Research Workshop Sessions

The theme of the Research Workshop Sessions is “Experimental models for investigating PFIC including precise diagnosis, pathophysiology, and developing treatments.” The goals of the Research Workshop are for researchers, physicians and industry to share and learn about new disease models, connect with each other to build next projects and to highlight challenges important to patients.

While patients and families are encouraged to attend the Research Workshop Sessions if they are interest, these talks have not been designed to be digestible for a lay audience. These are high-level scientific talks aimed at PFIC researchers and clinicians. At the end of the conference on Saturday, we will have a presentation of a lay-friendly summary of the Research Workshop, so patients and families don’t miss out on the cool research happening in PFIC!

Keynote Address: Understanding and mitigating hepatic bile acid accretion in pediatric cholestatic diseases

A hallmark of cholestatic disorders is the obligate intrahepatic accretion of bile acids. These molecules are natural components of liver cells and bile, but in situations like PFIC disorders , which are due to genetic variants in biliary transporters thereby reducing bile acid transport out of liver cells. Although the liver cell is poised to adapt and autoregulate normal “safe” bile acid concentrations, these capacities are overwhelmed when transporter genes do not function well. Understanding how the liver naturally adapts to retained bile acids, and where current and future therapies can target these transporters and enhance adaptive mechanisms, is a rational means to target cholestasis and help patients.

Speaker: Dr. Saul Karpen

Click To Read Speaker Bio

The focus of my research program is to provide a deeper understanding of the molecular mechanisms of cholestasis, with the objective of discovering novel molecular targets to treat cholestatic liver disease. I have employed a strong research interest in nuclear receptors and bile acid pathways to address root causes and targets for cholestatic diseases. My current laboratory and clinical research focus is on BA, the principal liver disease of infancy. Research arcs are directed towards addressing several crucial unknowns and unmet needs for this disease, which has been plagued by little progress in understanding its etiologies or developing effective therapeutics. Two BA research arcs are intended to provide discoveries along these lines: 1.) genetic etiologies, of which we have discovered, and validated in a mouse model, the first plausible etiologic gene for some BA patients, PKD1L1; and 2.) as lead of an international randomized placebo-controlled Phase 3 study of an ileal bile acid uptake inhibitor (NCT04336722) in BA.

On a national and international basis, I am engaged in the leadership of the AASLD (Senior Councilor, President in 2026), co-chair of the Liver Forum’s International Pediatric Cholestatic Disease Working Group and two NIDDK-supported consortia for liver disease: ChiLDReN and NASH CRN. At Emory/CHOA I am the inaugural Director for the Center for Gastroenterology, Endocrinology and Nutrition Innovation (GENI) which is focused upon the individual and societal impacts of obesity and metabolic health of children. Taken together, my overall goals are to develop integrative programs to improve children’s lives through research, discovery of rational therapeutic targets, and the development of safe and effective pharmaceuticals—all focused upon the unique and pressing needs of infants and children with liver diseases.

Note that as of March 1, 2024, Dr. Karpen will be the Chief Scientific Officer for the Stravitz-Sanyal Institute for Liver Disease and Metabolic Health at VCU in Richmond, VA. As of March 1, 2024 my email address will be saul.karpen@vcuhealth.org

A rapid mouse model system for PFIC by CRISPR-based multigenic knockout

This session will discuss newly established mouse models using CRISPR genome-editing technology. We will discuss liver injury induced by manipulation of bile acid metabolism with CRISPR-based rapid genome editing and “humanizing” bile acid profile.

Speaker: Dr. Hisamitsu Hayashi

Click To Read Speaker Bio

Dr. Hisamitsu Hayashi is a researcher and faculty member at the Laboratory of Molecular Pharmacokinetics, part of the Graduate School of Pharmaceutical Sciences at the University of Tokyo. He completed his Ph.D. in Pharmaceutical Sciences in 2010 at the University of Tokyo. His academic career has been anchored at The University of Tokyo, where he progressed from an Assistant Professor (2007–2021) to his current position as Associate Professor since 2021. In 2012, Dr. Hayashi served as a Visiting Assistant Professor at the Department of Psychiatry, University of California, San Francisco. Dr. Hayashi has been recognized for his research contributions, receiving the Research Encouragement Award from the Japan Research Foundation for Clinical Pharmacology in 2023 and The Young Scientists’ Award from the Japanese Ministry of Education, Culture, Sports,Science, and Technology in 2019. His research focuses on the development of novel therapies and diagnostic methods for pediatric liver diseases.

Novel mouse models for PFIC

In the last years, mutations in different genes mutations have been found that can cause progressive intrahepatic cholestasis. Without exception, all these subtypes of PFIC are very rare. To improve treatments for these patients it is very helpful to understand the mechanisms by which the specific gene mutations lead to impaired liver function. To better learn how the disease evolves and what therapeutic strategies could help, animal models can be generated in which the disease (or a specific mutation) is genetically induced. In these (mouse) models, bile formation and liver function can be investigated in much more detail than ever possible in patients and the effects of different experimental treatments can easier be assessed. Two mouse models for BSEP deficiency will be discussed, including with their pros and cons.

Speaker: Dr. Henkjan Verkade

Click To Read Speaker Bio

Website: https://www.rug.nl/staff/h.j.verkade/

Henkjan J. Verkade is a pediatric gastro/hepatologist at the Beatrix Children’s Hospital of the University Medical Center Groningen, The Netherlands. He received his PhD degree in Medicine cum laude at the University of Groningen on the thesis entitled “Lipid absorption and metabolism”. Henkjan Verkade was a post-doctoral fellow at the University of Alberta, Edmonton, Canada. In 2005 Verkade was appointed Professor of Pediatrics, pediatric gastroenterology/hepatology, at the University Medical Center Groningen.

Verkade has authored more than 300 peer-reviewed publications and more than 15 book chapters. Since 2019, he is associate editor of the Journal of Pediatric Gastroenterology and Nutrition.

IPSC Model-New Type of PFIC

We and others have shown that bi-allelic rare pathogenic variants in KIF12 cause high GGT cholestasis. KIF12 is a kinesin family member 12 and it has putatively been defined as a microtubule-associated motor protein. In the liver, KIF12 appears to be selectively expressed in cholangiocytes. Hence, we generated human induced pluripotent stem cell (hiPSC)-derived 2D and 3D biliary models with and without a homozygous p.Arg219* mutation in KIF12, which has been previously reported in patients. Using this KIF12 cell-based disease model, we have demonstrated that KIF12 mutant iCCs show an increased GGT activity and organelle mislocalization, possibly due to impairment in organelle trafficking. These findings provides new insights into human cholestatic liver disease pathogenesis.

Speaker: Dr. Silvia Vilarinho

Click To Read Speaker Bio

https://www.vilarinholab.org/
https://medicine.yale.edu/internal-medicine/digestivediseases/profile/silvia-vilarinho/

Using complementary experimental models to study new PFIC genes and variant

Summary statement: 30% patients with chronic intrahepatic cholestasis do not have mutations in known PFIC genes. Next-generation sequencing has accelerated identification of candidate genetic variants in patients that lack a molecular diagnosis. However, validating causality of novel variants is a main challenge in genetic diagnosis and hinders personalized treatment. In this talk, I will describe the pipeline we developed to functionally characterize the pathogenicity of novel loss-of-function PFIC variants. I will also present our recent study towards understanding the mechanism by which deficiency in the novel protein MRP9 causes PFIC-like symptoms in patients.

Speaker: Dr. Chunyue Yin

Click To Read Speaker Bio

https://www.cincinnatichildrens.org/research/divisions/g/gastroenterology/labs/yin

FIC1-ko iPSC model

Progressive familial intrahepatic cholestasis (PFIC) are a group of recessive disorders linked by the inability to appropriately excrete bile salts (BS) from hepatocytes. PFIC1 results from mutations in ATP8B1 encoding FIC1, an apical membrane aminophospholipid translocase. Unfortunately, a lack of reliable disease models has impeded scientific discovery and clinical advancement. We aim to explore how human induced pluripotent stem cells (hiPSCs) may be used to generate patient-specific liver tissue to model PFIC.

Speaker: Dr. Rodrigo Florentino

Click To Read Speaker Bio

https://livercenter.pitt.edu/people/rodrigo-m-florentino-phd

Research Interests:
Recently some point mutations have been associated with specific liver diseases. My interest is to understand the relationship between these mutations and the incidence of liver disease to find out the mechanism behind it. With the advances in induced pluripotent stem cell (iPS cell) technology and the ability to differentiate these cells into hepatic cells, such as hepatocytes, cholangiocytes and stellate cells, a new and a better model is available to study human liver diseases.

View Dr. Florentino’s publications on PubMed

Alagille model and development of new RNAi therapy

Discuss using gene silencing approaches to target known genetic modifiers of signaling pathways as potential treatment strategies for liver diseases and the importance of cell lineage specific delivery. An example will be presented using an antisense oligo (ASO) to improve the liver phenotypes in mouse models of Alagille syndrome (doi: 10.1097/HEP.0000000000000380).

Speaker: Dr. Stacey Huppert

Click To Read Speaker Bio

https://www.cincinnatichildrens.org/research/divisions/g/gastroenterology/labs/huppert

Dr. Stacey S. Huppert, PhD, is an Associate Professor in the Division of Gastroenterology, Hepatology & Nutrition at Cincinnati Children’s Hospital (CCHMC) and Department of Pediatrics at the University of Cincinnati College of Medicine. Her commitment to Notch signaling spans over twenty years since beginning her graduate training. In the laboratory of Dr. Marc A. T. Muskavitch at Indiana University, she demonstrated that Notch signaling exerts feedback regulation on ligand and receptor expression, and that the resultant asymmetries underlie proper cell fate determination. As a postdoctoral fellow in Dr. Raphael Kopan’s Laboratory and then as an Instructor in the Department of Molecular Biology and Pharmacology at Washington University School of Medicine, she continued to study Notch signaling mechanisms. Generating a mouse with a targeted mutation at the gamma-secretase cleavage site within Notch1, she demonstrated that intramembranous processing of Notch1 and release of the Notch intracellular domain (NICD) is indispensable for proper embryonic development.

Currently Dr. Huppert’s research program investigates hepatic cell plasticity and switching of liver cell identities to build missing liver bile ducts – formation of the three-dimensional hepatic architecture during development, homeostasis and regeneration. Her group uses multiple models of Alagille syndrome (ALGS) – mouse experimental and human induced pluripotent stem cells (iPSCs). They are focused on enhancing the potential of hepatocytes to restore bile ducts of patients with Alagille syndrome and other hepatobiliary diseases on two fronts: 1. Identify possible treatments for children whose liver disease is related to a lack of bile ducts by testing modifiers of Notch signaling, and 2. Correcting the bile duct supporting mesenchymal cell niche.

In vivo selection for cell and gene therapy in the liver

Many promising gene therapy and cell transplantation approaches to treating genetic liver diseases are hampered by low efficiency. This problem can be overcome by in vivo selection of therapeutic hepatocytes. Methods to achieve therapeutic selection will be shown and discussed.

Speaker: Dr. Markus Grompe

Click To Read Speaker Bio

https://www.ohsu.edu/people/markus-grompe-md

Dr. Markus Grompe is the Ray Hickey Professor and Director of the Papé Family Pediatric Research Institute at Oregon Health & Science University in Portland, Oregon, USA. His research has focused on the use of in vivo selection to enhance gene and cell transplantation therapy for inherited diseases. Hepatic stem cells and their use in therapeutic liver repopulation are a main focus. To study the properties of human cells in a physiologic setting the laboratory has developed murine models supporting the expansion of human stem cells in transgenic mice. These humanized mice are an ideal platform for the development for novel therapeutics, including small molecules, gene therapy vectors and cells. He has published over 200 peer-reviewed articles and holds numerous patents.

Gene therapy targeting cholangiocytes

Human liver gene therapy with adeno-associated virus (AAV) vectors has reached a pivotal stage, marked by FDA approval for hemophilias but also fatalities from liver toxicity. Accurate prediction of AAV vector performance in the human liver facilitates the development of safe and effective liver gene therapies meeting disease-specific demands.

Speaker: Dr. Holger Willenbring

Click To Read Speaker Bio

https://willenbringlab.ucsf.edu

Research Overview
Our research is aimed at developing new therapies for patients with severe liver diseases. To restore liver function in patients with liver failure, we are working on generating hepatocytes from human pluripotent stem cells or by reprogramming of readily accessible human cell types. To be therapeutically effective, these cells need to replicate both function and the ability to proliferate of primary human hepatocytes. To establish and improve protocols for the production of such cells, we have been working on obtaining a detailed molecular understanding of hepatocyte differentiation and regeneration. For this, we are using mouse models for liver cell lineage tracing developed in our laboratory. In addition, we are using rigorous animal models of human liver failure to test the therapeutic efficacy of our surrogate hepatocytes. While developing novel liver cell therapies is our main focus, we are also using hepatocytes derived from human pluripotent stem cells or by reprogramming to generate in vitro and in vivo liver disease models. Another goal of our laboratory is to determine the origin and follow the fate of liver cancer-initiating cells with the goal to identify the molecular mechanisms that drive liver cancer formation and progression. For this, we are using new mouse models generated in our laboratory. By obtaining an improved understanding of hepatocarcinogenesis, we hope to contribute to the development of strategies for early detection and effective eradication of liver cancer.

Jump to:

Family Sessions

Family-Researcher Roundtables

Poster Abstracts

Family-Researcher Roundtable Discussions

The Roundtable Discussions are designed for brainstorming topics that PFIC Network and researchers can explore, inform work and prioritize needs by engaging in guided conversations together. The overall objective is to gain strategic insight into our community priorities over the next 3-5 years to support clinical care guidelines and therapeutics development that align with patient priorities.

Roundtable Discussion #1

Patient-Centered Outcomes Research Priorities in PFIC

Facilitators: Alexandra Perez, Dr. Jim Squires

Last year PFIC Network received a Eugene Washington Engagement Award from the Patient Centered Outcomes Research Institute (PCORI) (PCORI grant EASO-30450). Our project is titled “IMPACT” (Identifying research targets by Merging Patient And Clinician Treatment information). It aims at preparing the PFIC community to participate as equal partners in patient-centered research studies that focus on PFIC treatments.

During Roundtable #1, IMPACT Project Team members will talk about the progress-to-date. One of the most important milestones is the IMPACT web app which launches at the conference. The webapp is an interactive platform that lets patients enter their experiences with the different PFIC treatments and medications, and that provides summarized treatment information. The last hour of the session will be an open discussion how patient-centered outcomes research (PCOR) can improve decision making between currently available PFIC treatments.

Watch a recording of the IMPACT presentation and app preview in our Webinar Library!

Read a summary of the Roundtable Discussion!

Speaker Bio- Alexandra Perez

Alex is the Community Focus Group Facilitator for Project IMPACT. She will be co-leading an IMPACT-related roundtable discussion. She is the mother of a child with PFIC.

Speaker Bio- Dr. Jim Squires

https://livercenter.pitt.edu/people/james-squires-md-ms

Dr. Squires earned his medical degree from the University of Texas and went on to complete his training in general pediatrics at the Cincinnati Children’s Hospital Medical Center (CCHMC). Following residency, he completed fellowships in both pediatric gastroenterology and pediatric advanced/transplant hepatology at CCHMC and completed a Masters in clinical and translational at the University of Cincinnati. Following completion of his training, Dr. Squires joined the faculty at the Children’s Hospital of Pittsburgh in 2015 where he is currently an Associate Professor in Pediatrics, the Director of the Pediatric Advanced/Transplant Hepatology Fellowship, and Associate Medical Director of Hepatology.

Dr. Squires remains active in both clinical and research pursuits. He is a co-investigator in the Children Liver Disease Research Network, an NIH funded consortium working to improve the lives of children with rare cholestatic liver diseases. He is also a member of the Society of Pediatric Liver Transplant, a multifaceted organization focused on improving outcomes for children receiving liver transplantation. He is the Clinical Lead for the Starzl Network for Excellence in Liver Transplantation, a novel learning health network of leading pediatric transplant institutions committed to continuous improvement until every child can achieve a long and healthy life and has received funding from the Patient-Centered Outcomes Research Institute to advance this work. Other current interests include metabolic liver disease, acute liver failure, and liver transplant.

Roundtable Discussion #2

The Benefits and Risks of PFIC Clinical Research

Facilitators: Laura Susoi, Dr. Richard Thompson

Roundtable #2 focuses on discussing clinical research and therapeutic development in the context of Progressive Familial Intrahepatic Cholestasis (PFIC). The session aims to engage the PFIC community in defining the benefits and risks of clinical trial participation and discussing the relative risk tolerance of the community regarding potential future therapies. The session also includes learning objectives aimed at facilitating a meaningful discussion regarding risk tolerance, mitigation in clinical research, and the importance of patient perspectives in clinical trials and therapeutic development.

The content of the accredited activity is limited to basic science research, such as pre-clinical research and drug discovery, or the methodologies of research, and will not make treatment or care recommendations.

Watch a recording of the opening presentation in our Webinar Library!

Speaker Bio- Laura Susoi

Laura is the mother of a PFIC 2 child, Louka. She lives in Canada.

Speaker Bio- Dr. Richard Thompson

https://www.kcl.ac.uk/people/richard-thompson

Dr. Thompson specialises in paediatric liver disease. In particular he is interested in genetic disease, both in children and adults. His group have identified several disease genes, and have established important genotype/phenotype correlations. He is also the Clinical Lead for the Liver Molecular Genetics service. Dr. Thompson is also a Professor of Molecular Hepatology at King’s College London.

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Poster Session Abstracts

Long-Term Maintenance of Response and Improved Liver Health With Maralixibat in Patients With Progressive Familial Intrahepatic Cholestasis (PFIC): 2-Year Data From the MARCH-ON Study

Authors & Affiliations

Authors: Alexander G. Miethke,¹ Adib Moukarzel,² Gilda Porta,³ Joshue Covarrubias Esquer,⁴ Piotr Czubkowski,⁵ Felipe Ordonez,⁶ Antonella Mosca,⁷ Amal A. Aqul,⁸ Robert H. Squires,⁹ Etienne Sokal,¹⁰ Daniel D’Agostino,¹¹ Ulrich Baumann,¹² Lorenzo D’Antiga,¹³ Nagraj Kasi,¹⁴ Nolwenn Laborde,¹⁵ Cigdem Arıkan,¹⁶ Chuan-Hao Lin,¹⁷ Susan M. Gilmour,¹⁸ Naveen Mittal,¹⁹ Fang Kuan Chiou,²⁰ Simon P. Horslen,⁹ Wolf-Dietrich Huber,²¹ Tiago Nunes,²² Anamaria Lascau,²²Lara Longpre,²² Douglas B. Mogul,²² Marshall Baek,²²Pamela Vig,²² Vera F. Hupertz,²³ Regino Gonzalez-Peralta,²⁴ Udeme Ekong,²⁵ Jane Hartley,²⁶ Noemie Laverdure,²⁷ Nadia Ovchinsky,²⁸ Richard J. Thompson²⁹

Affiliations: ¹Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio; ²Hôtel Dieu de France Saint Joseph University Hospital, Beirut, Lebanon; ³Hospital Sírio-Libanês, São Paulo, Brazil; ⁴Nois de México SA de CV, Jalisco, Mexico; ⁵Gastroenterology, Hepatology, Nutritional Disorders and Pediatrics, The Children’s Memorial Health Institute, Warsaw, Poland; ⁶Cardioinfantil Foundation-La Cardio, Bogotá, Colombia; ⁷Ospedale Pediatrico Bambino Gesù Irccs, Lazio, Italy; ⁸University of Texas Southwestern Medical Center, Dallas, Texas; ⁹UPMC Children’s Hospital of Pittsburgh, Pediatrics, Pittsburgh, Pennsylvania; ¹⁰UCLouvain, Cliniques Universitaires St Luc, Pediatric Hepatology, Brussels, Belgium; ¹¹Hospital Italiano de Buenos Aires, Buenos Aires, Argentina; ¹²Hannover Medical School, Pediatric Gastroenterology and Hepatology, Hannover, Germany; ¹³Paediatric Hepatology, Gastroenterology and Transplantation, Hospital Papa Giovanni XXIII, Bergamo, Italy; ¹⁴Medical University of South Carolina, Charleston, South Carolina; ¹⁵Hôpital des Enfants – CHU Toulouse, Toulouse, France; ¹⁶Koc University School of Medicine, Istanbul, Turkey; ¹⁷Children’s Hospital Los Angeles, Los Angeles, California; ¹⁸University of Alberta, Pediatrics, Edmonton, Alberta, Canada; ¹⁹University of Texas Health Science Center at San Antonio, San Antonio, Texas; ²⁰KK Women’s and Children’s Hospital, Singapore; ²¹Medical University of Vienna, Vienna, Austria; ²²Mirum Pharmaceuticals, Inc., Foster City, California; ²³Cleveland Clinic Children’s, Cleveland, Ohio; ²⁴AdventHealth for Children and AdventHealth Transplant Institute, Pediatric Gastroenterology, Hepatology, and Liver Transplant, Orlando, Florida; ²⁵MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital, Washington, DC; ²⁶Birmingham Women and Children’s Hospital, Birmingham, United Kingdom; ²⁷Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Pediatric Hepato Gastroenterology and Nutrition Unit, Lyon, France; ²⁸New York University Grossman School of Medicine, New York, New York; ²⁹Institute of Liver Studies, King’s College London, London, United Kingdom

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Background

PFIC is a group of genetic disorders resulting in disrupted bile composition, cholestasis, and pruritus. Maralixibat (MRX), a minimally absorbed IBAT inhibitor which prevents enterohepatic bile acid recirculation. In the 26-week placebo-controlled MARCH Phase 3 study, MRX at 570 μg/kg BID demonstrated significant improvements in pruritus, serum bile acids (sBA), total bilirubin (TB) and growth in patients across the broadest range of PFIC types studied to date. We report on long-term maintenance of effect of up to 2 years of treatment with MRX in MARCH-ON, an open-label, long-term extension study of MARCH.

Methods:

Long-term maintenance of response was assessed for patients who were originally randomized to receive MRX in MARCH and continued with treatment in MARCH-ON (MRX-MRX group: n=33), and for patients who received placebo (PBO) in the MARCH study and switched to open-label MRX in MARCH-ON (PBO-MRX group: n=27). Assessments included: pruritus, sBA, TB, growth z-scores, and incidence of treatment-emergent adverse events (TEAEs). Baseline (BL) was defined as the start of MRX for each group.

Results:

For the MRX-MRX group, the median (min, max) time on MRX was 638 days (10, 1135). Significant improvements observed in the first 26 weeks of the MARCH study were sustained through Week 104 in MARCH-ON for pruritus (-2.03, p<0.0001), sBA (-166 μmol/L, p=0.003), TB (-1.6 mg/dL, p=0.02), and growth (height z-score: +0.40, p=0.046; weight z-score: +0.52, p=0.01). In the PBO-MRX group, the median time on MRX was 456 days (22, 720). Significant improvements through Week 52 for pruritus (-1.1, p=0.0001), sBA (-71 μmol/L, p=0.03), and growth (height z-score: +0.37, p=0.01; weight z-score: +0.32, p=0.03) were in line with observations from the initial MARCH MRX group. Additionally, numeric reductions in TB (-0.4 mg/dL; p=0.7) were observed. No new safety signals were identified. The most common TEAEs were GI-related with diarrhea (50%) being mostly mild and transient.

Conclusion:

Significant and sustained improvements in pruritus, sBA, TB, and growth are observed with up to 2 years of MRX treatment. across the broadest range of genetic PFIC types studied to date. These data suggest overall improved liver health with MRX treatment which can be maintained long-term.

Development and Implementation of the CURL Gene Panel for Rare Liver Diseases in Pediatric Patients

Authors & Affiliations

Authors: Akihiro Asai ^1,2; William Balistreri^1,2; Chunyue Yin^1,2; Wenying Zhang^1,2; Emily Vincent¹

Affiliations: 1: Cincinnati Children’s Hospital Medical Center, 2: University of Cincinnati College of Medicine.

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The Center for Undiagnosed and Rare Liver Disease (CURL) at Cincinnati Children’s Hospital Medical Center, introduces Cincinnati’s Undiagnosed and Rare Disease Gene Panel (CURL Panel) to enhance the diagnosis of rare liver diseases in pediatric patients. Traditional diagnostic methods often fall short, leaving many patients without a definitive diagnosis. The CURL Panel focuses on children with cholestasis to ensure targeted application.

Distinguished from current genetic tests that frequently result in variants of unknown significance (VOUS) without further analysis, the CURL Panel analyzes over 1400 genes related to cholestatic liver disease. It offers an unprecedented approach by providing access to whole exome sequencing (WES) and a research arm utilizing a validation platform including CRISPR in zebrafish and human hepatocyte models using induced pluripotent stem cells. This comprehensive strategy aims to furnish clear diagnoses, uncover new genetic variants for future diagnostics, and facilitate personalized care based on patient phenotypes.

A pilot program will test a cohort of 10-20 patients, allowing the team to refine methodologies, criteria, and infrastructure for broader applications. This initiative represents a significant advancement in the field, promising improved diagnostic accuracy and therapeutic targeting for pediatric patients with rare liver diseases.

Outcomes in adult patients with progressive familial intrahepatic cholestasis treated with odevixibat: Subgroup analysis from the PEDFIC 2 study

Authors, Affiliations & Conflicts of Interest

Authors: Bertrand Roquelaure¹, Henkjan J. Verkade², Kathleen M. Loomes³, Janis M. Stoll⁴, Christine Clemson⁵*, Jan P. Mattsson⁵*, Danielle Dray⁵, Lisa Cimperman⁵, Tao Gu⁵

Affiliations: ¹CHU, Hospital de la Timone, Marseille, France; ²Pediatric Gastroenterology/Hepatology, Department of Pediatrics, University of Groningen, Beatrix Children’s Hospital/University Medical Center Groningen, Groningen, the Netherlands; ³Children’s Hospital of Philadelphia, Philadelphia, PA, USA; ⁴Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, USA;⁵Ipsen, Cambridge, MA, USA

*Employee of Albireo Pharma, Inc., an Ipsen company, at the time of the study

CONFLICTS OF INTEREST

B. Roquelaure and J. M. Stoll: Nothing to disclose

H. J. Verkade: Ausnutria BV, Albireo Pharma, an Ipsen company, Danone Nutricia Research, Intercept, Mirum, Orphalan, and Vivet – Consultant

K. M. Loomes: Albireo Pharma, an Ipsen company, Mirum, and Travere Therapeutics – Consultant

C. Clemson and Jan P. Mattsson: Albireo Pharma, an Ipsen company – Previous employmentDanielle Dray, Lisa Cimperman, and T. Gu: Ipsen – Employment

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Background: Progressive familial intrahepatic cholestasis (PFIC) is a group of rare genetic liver diseases characterized by cholestasis, pruritus, and progressive liver damage. PFIC symptoms typically present in infancy; infrequently, symptom onset may occur in adulthood. To improve our understanding of treatment of adults with odevixibat (an ileal bile acid transporter inhibitor), we examined its efficacy and safety in adult patients from the PEDFIC 2 trial (NCT03659916).

Methods: This analysis of adult patients enrolled in PEDFIC 2 (a 72-week, open-label extension study in patients with PFIC receiving odevixibat 120 μg/kg once-daily) evaluated patient-reported pruritus scores (range, 0–4; higher scores indicate worse symptoms), serum bile acid (sBA) levels, hepatic biochemical parameters (total bilirubin and alanine aminotransferase [ALT] levels), and treatment-emergent adverse events (TEAEs). Data cutoff is January 31, 2022.

Results: 5 adult patients with PFIC (mean age, 23.3 [range, 19.5–26] years; 40% female) had enrolled in PEDFIC 2; 3 had PFIC1 and 2 had PFIC2. At baseline, all patients had elevated sBAs and moderate-to-severe pruritus. Mean exposure to odevixibat was 36 (range, 24–65) weeks. Several patients had reductions in sBA levels, pruritus scores, total bilirubin levels, and/or ALT, despite varying sBA levels over time. Three patients (60%) had ≥1 TEAE (most mild to moderate), and 2 experienced a serious TEAE; none were considered drug-related. No patient discontinued due to TEAEs.

Conclusion: Several adult patients with PFIC experienced clinical benefits with odevixibat, including reductions in sBAs, pruritus, and/or improvements in hepatic parameters. No TEAEs were considered to be drug related.

BSEP v2.0: Using AI-Assisted Predictions of Molecular Evolution for the Effective Treatment of Progressive Familial Intrahepatic Cholestasis 2 (PFIC 2)

Authors & Affiliations

Authors: Khartik Uppalapati (1), Viraj Kamath (1), Akihiro Asai

Affiliations: 1: Oakton High School

Contact information: Akihiro Asai, aki4810@gmail.com

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Progressive Familial Intrahepatic Cholestasis (PFIC) 2 is a high-mortality liver condition that manifests as a result of variants in the ABCB11 gene, which encodes for the Bile Salt Export Pump (BSEP) protein, the primary transporter responsible for the ATP-based secretion of bile salts from hepatocytes. The aim of our project is to develop a novel protein with improved ATP Binding capacity for efficient bile acid secretion.

Methods: A Feedforward Neural Network (FNN) model was trained on 732 proteins with varying ATP binding activity which were annotated based on Binding Affinity, Stability, and Binding Site-ATP distances. Mutagenesis was carried out in silico over 10 generations on the Walker-A and Walker-B motifs of BSEP’s NBD (nucleotide-binding domain), simulating molecular evolution. Molecular Docking was used to compute binding affinity, and Molecular Dynamics simulations were used to calculate Binding Site-ATP molecular distances. Virtual Screening was conducted through evaluation from the FNN Model, utilizing computed binding properties as inputs. Top mutants were scored against BSEP and their crystal structures were analyzed using ColabFold. Results: Mutagenesis at position X (undisclosed) with glycine substitutions was shown to have 51.32% improved binding capabilities due to its simple structure allowing for stronger bonds between amino acids to ATP. Our FNN model achieved 81% accuracy on ground truth datasets with a bias towards promoting Alpha Helix stability over other metrics.

Conclusion: AI-assisted computational mutagenesis can simulate molecular evolution and dramatically shorten the investigation time to version up BSEP when followed by biological validation assays.

Lock & Key of Recurrent Bile Salt Export Pump (BSEP) Deficiency: Quantification and Epitope Identification of anti-BSEP autoantibodies

Authors & Affiliations

Authors: Akihiro Asai ^1,2; Hisamitsu Hayashi³, Chie Naito¹, Alyssa Takahashi¹

Affiliations: 1: Cincinnati Children’s Hospital Medical Center, 2: University of Cincinnati College of Medicine. 3: Graduate School of Pharmaceutical Sciences, The University of Tokyo

Contact information:

Akihiro Asai,

Division of Gastroenterology, Hepatology and Nutrition

Cincinnati Children’s Hospital Medical Center

Akihiro.asai@cchmc.org

Phone:513-517-1013

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Progressive familial intrahepatic cholestasis 2 (PFIC2) is caused by mutations in the ABCB11 gene, leading to BSEP deficiency and severe liver dysfunction. An estimated 8% of PFIC2 patients develop autoantibodies against BSEP post-transplant, resulting in “recurrent BSEP deficiency.” Our objective is to quantitatively measure these autoantibodies in serum and identify responsible epitopes to enhance post-transplant monitoring.

Methods: We developed a novel ELISA to quantify BSEP autoantibodies in patient sera, utilizing synthesized whole-length BSEP or BSEP segments known to contain epitopes. Serum from three patients with PFIC2 after liver transplant, clinically diagnosed or suspected to have “recurrent BSEP deficiency”, was analyzed.

Results: Using whole-length BSEP, we quantified auto-antibodies in patients’ sera, and clinical symptoms and laboratory data were correlated. We found significant autoantibody reactivity against a BSEP segment (616-746aa) in one patient’s serum, while no reactivity was found in the other patients’ sera. However, the reactivity against this segment was also present in healthy serum, suggesting its non-specific reactivity in disease pathology. Weak signals from other segments hinted at the presence of autoantibodies but were insufficient for quantification, possibly due to short peptide lengths affecting antibody affinity.Conclusion: Our ELISA method enables the quantitative detection of anti-BSEP autoantibodies and epitope identification in PFIC2 patients’ sera. This advancement allows for reliable monitoring of autoantibody development post-transplant, contributing to the prevention of recurrent BSEP deficiency.

Tight junction protein 1&2 regulate bile canalicular formation during hepatocyte differentiation and self-organization

Authors & Affiliations

Authors: Karis Kosar

Affiliations: Cincinnati Children’s Hospital and Medical Center

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Background & Aims: Newborns with deficient tight junction protein 2 (TJP2) develop a subtype of progressive familial intrahepatic cholestasis (PFIC-TJP2), which manifests as neonatal cholestasis that progresses to cirrhosis, while other organs often remain unaffected. Bile flow originates at the hepatocyte canalicular membrane, which forms the bile canaliculus (BC), a specialized bile draining “channel” between hepatocytes demarcated by tight junctions built with scaffolding proteins, TJP1&2, and transmembrane junction proteins. We found that PFIC-TJP2 patients have disrupted BC structures in liver biopsies and increased bile concentrations in both liver tissue and blood serum. Thus, we hypothesized that TJP1&2 play critical roles in BC formation during hepatocyte differentiation.

Approach & Results: To test this hypothesis, we combined novel induced pluripotent stem cell (iPSC) differentiation and culturing methods, to generate canalicular tubes between opposing induced hepatocytes (iHeps) capable of transporting bile. We then genome edited iPSCs to disrupt TJP1&2 separately, through patient relevant truncation or complete knock-out, then cultured these cells to form BC. We found that TJP1 deficiency showed cell death in the early stage of hepatocyte differentiation. TJP2 deficiency showed disrupted BC formation, resulting in shortened and rosette-like BC but did not affect hepatocyte bile excretion into these short BC structures. We found that treating these cells with mRNA lengthens these disrupted BC, to a more WT-like phenotype.

Conclusions: These findings indicate that TJP1&2 deficiency disrupts BC network formation which likely causes a build-up of bile in the disrupted BC, resulting in cholestatic injury and ultimate liver failure observed in PFIC-TJP2 patients. Additionally, we found that treating TJP1&2 deficient iHeps with TJP1&2 mRNA rescues disrupted BC structure can could offer a novel method for therapy this ultra-rare liver disease.

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